Karl Grassmann's 1896 paper “critical overview of contemporary theories of the heredity of the psychoses”

Four years before the rediscovery of Mendel's work in 1900, Karl Grassmann published a detailed, scholarly review of the heredity of psychosis which we here review. A full translation is in the appendix. We emphasize seven major conclusions from this review. First, while recognizing the key importance of heredity in the etiology of psychosis. Grassmann was critical of many of the highly speculative extant theories. Second, he reviewed most of the major methodologic concerns in the literature from what kinds of heredity to investigate to the problems with the global use of insanity as a diagnostic category. Third, he discussed in detail genetic theories associated with Degeneration theory, maintaining considerable skepticism. Fourth, he recognized nongenetic contribution to familial transmission. Fifth, he reviewed evidence for both homogeneous and heterogeneous transmission of forms of mental illness in families, suggesting that both were important. Sixth, while he noted that mania, melancholia, and cyclothymia commonly replaced each other in families, Verrücktheit (delusional psychoses) rarely co‐segregated in families with these mood disorders. Seventh, Grassmann, like other 19th century writers, saw relatives to be of value only in assessing the level of hereditary predisposition in patients and had limited appreciation of the need for controlled studies.

and we follow that organization in our review. But first, we provide a biographical sketch of our author, based largely on a 1933 obituary by Bergeat (1933). Karl Grassmann (20 September 1867-7 May 1933  dependents. Later he belonged to the administration of the committee for doctors' support, also for the Bavarian State Chamber of Physicians, the regional professional court, and for more than 25 years, the new association of Munich Medical Practitioners (Bergeat, 1933, p. 856).

| BIOGRAPHICAL SKETCH
Colleagues viewed him as having …extraordinary expertise, legal knowledge, certain judgment, incorruptible objectivity, as well as incredible conscientiousness in his participation in the various endeavors, despite his own professional overloading (Bergeat, 1933, p. 856).
He became well-known far beyond Munich as a result of his vast number of publications, including more than 50 papers which "… for a practicing doctor is a massive output (Bergeat, 1933, p. 856)." In addition to writing about his specialty of cardiology, he wrote about a wide array of other areas of medicine and related topics especially considering their scope. "Besides about 30 in the cardiac field, there were another 20 of varied general content, such as appraisal, quackery, status questions, school health care, etc. much of which remained relevant in his time and was frequently cited in the literature." Bergeat notes particularly that "Grassmann throughout his life retained the pronounced desire and the gift to keep learning, even in the most modern fields (Bergeat, 1933, p. 856)." Grassmann appeared to be an auto-didact and Bergeat does not comment specifically about his work in psychiatric genetics. We do know that in the mid-1890s, when he was working on the article we review here, Grassmann was studying in Berlin and Munich with Carl Gerhardt and Albert Krecke. At that time, both were investigating topics related to neuropathology and psychiatry, with Gerhardt publishing articles on "diseases of the brain arteries" and "syphilis and the spinal cord" (Strassburg, 2020) and Krecke on traumatic neurosis and hysteria.
We would speculate that, as an ambitious and scholarly 29 yearold, whose future career path was not yet determined, Grossmann became interested in the literature on the heredity of insanity, reading widely and then writing this article, which he was able to publish in a venerated specialty journal. A few years later, his career took a different turn (toward internal medicine and cardiology), and he did not return to this topic again.

| INTRODUCTION
The thoughtful and skeptical tone of this article is well captured in this section of the introduction (italics here and later in this essay added for emphasis): As is well known, knowledge of the causes of diseases has made a greater progress in the course of the last few decades than it had been granted in as many centuries, and in the field of infectious diseases scientific research has successfully solved a series of etiological riddles with the aid of the microscope and animal experiments. However, … such a beneficial revolution has not come to other branches of etiological research, and in these latter the traditional problems have been solved by the hitherto existing means and incrementally on the long-established paths of gradual clarification.
Although Krafft-Ebing proudly stated that "the etiology of insanity is probably better known than that of most other diseases," this joy in victory is unfortunately to be measured in terms of its justification against the relatively lesser etiological knowledge of other disciplines.
Within this context, even a single causal factor of the psychoses, such as heredity, still presents a long series of unsolved and obscure questions, the existence of which fits poorly with the above statement. Although, as a result of the lively attention of current scientific research regarding the difficult question of the etiology of mental diseases, both a number of views previously held to be valid have been corrected and a number of new facts have been discovered. Statistics, an indispensable aid in this field, has also in public, state and community facilities currently received a more secure basis. However, with regard to heredity, which according to general opinion plays a main role in the pathogenesis of psychoses, the opinions in circulation today, on closer inspection, vary considerably and the arbitrary treatment and amateurish vagueness, with which this "material" has passed into the products of current literature indicates how much speculation and how many hypotheses are still being spread (Grassmann, 1896, pp. 960-1).
Grassman begins with the transformative effect of the microbial theories on the understanding, treatment and nosology of infectious diseases in the latter third of the 19th century, a view widely supported in modern medical histories of disease (Carter, 2003). Despite the optimistic quote from the leading German neuropsychiatrist Krafft-Ebing (who was the most prominent German language Alienist prior to the rise to prominence of Kraepelin in the late 1880s and 1890s), Grassman is considerably more critical of the current state of knowledge regarding how genetic factors impact on psychotic illness.
He praises the rise in statistical analysis of the effects of heredity in large asylum samples which generally increased in size and statistical sophistication over the 19th century. But he is biting in his views of the current state of the field of psychiatric genetics (e.g., "arbitrary treatment and amateurish vagueness" … how much speculation and how many hypotheses are still being spread.") He turns to trenchant summary of the methodological problems of psychiatric genetics research: Apart from the fact that all etiological factors for mental disorders are difficult to study because of their complexity, there is also the fact that the question of heredity, according to its nature, requires not only the life work of individuals, but also the purposeful cooperation of several generations of reliable researchers with the same points of view. There is also the fact that it cannot much be promoted experimentally and in the laboratory at present (Grassmann, 1896, p. 961).
He then declares the goal of his review In view of these difficulties, it may not seem entirely worthless to try to do a brief overview of the main points of today's theory of the heredity of psychoses, to juxtapose the pros and cons of the prevailing opinions, to emphasize what is certain from the stream of what is still uncertain, and to examine the individual directions and the results of current research with regard to their justification (Grassmann, 1896 Grassmann notes the few critics of this perspective but concludes that their arguments largely "fail." He cites the consensus on this point of the last two generations of researchers: "the older and younger researchers agree at least that heredity is of great importance for the genesis of the psychoses (Grassmann, 1896, p. 962)." At this point, he raises a major theme of his essay-the influence of the French school of degeneration theorists-who have "made the question of the general meaning of heredity a much broader one (Grassmann, 1896, p. 963)." (For further details on degeneration theory, see Kendler (2022) and Pick (1996)). They hypothesize that the disorders in the psychopathic and neuropathic regions belong to a family of diseases that belong together, whose individual members can represent and replace one another in and through the workings of heredity (Grassmann, 1896, p. 963).
Against this expansion of the views of genetic effects, Grassman contrasts the opinion of the influential German psychiatrist/ neuroanatomist Meynert who argues against this way of thinking about etiology, which generalizes in an almost unjudgmental way a completely mystical concept of heredity, and is lacking in all mechanical points of origin (Grassmann, 1896, p. 963).
To this Grassman adds his own critical view: In view of the theses of the French school, it is easy to understand how Meynert could come to this sharp condemnation, which is directed against going too far with theoretical speculations that do not have a secure basis (Grassmann, 1896, p. 963).
He returns several times to these issues later in the review.

| Chapter 1-Section 1-The concept and extent of heredity
This section begins by a description of three then common forms of "heredity": "direct"-defined as parent-offspring transmission, "atavistic"-largely resemblance between grandparents and grandchildren but other ascendants might be included and "collateral" heredity, which refers resemblance among siblings (although this might sometimes include cousins). Grassman argues that only including direct inheritance-a not uncommon approach in the earlier literature-is too restrictive an approach.
He similarity rejects proposed theories of inheritance that require the age of onset in relatives to be similar or require, in parentoffspring transmission, the parent to have been affected at the time of conception. He concludes that Completely certain and incontrovertible norms under which conditions a pathological property of the descendant must be regarded as "inherited" in the objective sense have not yet been set up (Grassmann, 1896, p. 964).
In determining the clinical role of heredity, Grassman criticizes the prevailing standard which he terms the "method of exclusion"that is, in patients with mentally ill relatives and no evidence of other causes of illness, heredity is assumed to be the cause. This approach, he argues "only enables the certainty of indirect proof (Grassmann, 1896, p. 965)."

| Chapter 1-Section 2-Facts and theories about heredity
Grassmann begins this subsection bemoaning the foundational ignorance about the underlying nature of genetic transmission. In discussing genetic influences on the psychoses, he writes that "I cannot leave these general questions entirely untouched, since they are the basis for many detailed statements which will be discussed later (Grassmann, 1896, p. 965)." He then presents a review and acceptance of quite recent research about the biological basis of genetic effects, citing the main point of recent research being that … the nuclei of the sex cells represent the carriers of heredity. These are highly organized formations which never give up their organization but act on one another as morphological parts-v. Nägeli has explained it as a physiological impossibility that predispositions can be transmitted by means of dissolved substances. The general and individual characteristics appearing in the progeny as it develops are due to the molecular structure of the nuclei (Grassmann, 1896, pp. 995-996).
What transpires is a quite informed discussion of earlier theories of genetic transmission, including Darwin's pangenesis. But he then turns to more recent work, especially that of August Weissmann on the "continuity of the germ plasm" (Mayr, 2004) and rightly points out the significance of this work for his topic as Weismann denied the question, which is extremely important for the theory of heredity in psychoses, whether acquired characteristics can be transmitted through heredity (Grassmann, 1896, p. 967).
Across the 19th century in the fields of medical genetics, psychiatric genetics and medical more broadly (including major medical figures such as Virchow), inheritance of acquired characteristics (IAC) was accepted as a given by the vast majority of investigators. It took several decades for the careful work of Weissmann to convince the field that genetic material was passed in one consecutive line from gamete to gamete, ruling out the possibility that life experience or disease could in anyway impact on the germline. Indeed, Grassmann, writing in 1896, declared the topic far from closed, noting the particular support for the IAC coming from French investigators: However, the decisive question of the hereditary nature of the psychoses regarding the inheritance of acquired characteristics has not been resolved, but is still the subject of lively debate (Grassmann, 1896, pp. 968-9).

| CHAPTER 2-THE HERITABLE QUALITIES OF PSYCHOPATHIC ASCENDANTS
Grassman begins his second chapter by succinctly summarizing the main question to be addressed: In order to determine the extent and importance of heredity in the etiology of mental diseases, the decisive factor is the form in which those pathological characteristics of the ascendants appear which give rise to the disease in the offspring. Our view of this will not only depend on the numerical expression of the weight of that etiological factor, but the entire research into the hereditary nature of the psychoses is decisively influenced by it (Grassmann, 1896, p. 969).
That is, what are the clinical features and/or personality traits of ascendants, especially parents that convey increased risk for psychosis to their descendants? Grassman gives a wide-ranging review of the recent literature on this central question. He starts by summarizing his views about what we have called homogenous or "like to like" transmission across generations (Kendler, 2021a).
The circumstance that, from a line of ancestors showing the symptoms of one of the distinct forms of insanity, for example, melancholy, paranoia, mania, feeblemindedness, etc., the disposition to a similar disease in their offspring has so undeniably been evidenced by the frequency of experiences in this regard, that the causal connection between the diseases of the successive generations is assumed to be self-evident (Grassmann, 1896, p. 970).
But then, citing a wide range of German and French authors, Grassman notes support for the idea that a range of nonpsychotic eccentricities in ascendants also predispose to insanity in their descendants: Even lower degrees of pathologically altered mental functions, which are expressed in peculiarities in the formation of character, life conduct, conspicuous unevenness in the development of the intellect, etc., in short, in characteristics which cause the persons concerned to be considered to be "originals," religious and political fanatics, oddballs and the like, have been explained as the source of heredity [of insanity] (Grassmann, 1896, p. 970).
After briefly reviewing the divergence of opinions about whether "anatomical brain diseases," especially apoplexy, in ascendants predispose to insanity in descendants, Grassmann approaches the large topic of a much wider set of conditions that might index an hereditary predisposition to psychosis: Since the so-called major neuroses, which are so regularly found in the genealogical trees of burdened families (e.g., epilepsy, hysteria, chorea), function as a pathological link in the pathogenetic series of the affected generations, it has long since become established as a result of a rich experience by means of case studies (Grassmann, 1896, p. 971).
And from there, after the major degeneration theorists, both French and German (e.g., Morel, Moreau, Magnan, Legrand du Saulle, and Krafft-Ebing) he writes This fact has suggested that all anomalies of the nervous system, not only those localized in the brain, constitute a predisposition to the development of mental diseases … and others, have closely pursued the idea of a familial connection of mental disorders and nervous diseases. For a large number of the latter, for example, tetany, eclampsia, facial hemiatrophy, syringomyelia, progressive muscular atrophy, Basedow's [Grave's] disease, attempts have been made to provide statistical evidence that their carriers are a source of mental illness in offspring (Grassmann, 1896, p. 971).
In the remainder of this section, he reviews evidence that genius, crime, suicide, alcoholism, and drug abuse increase the risk for psychosis in descendants. A few sections in this discussion are particularly worthy of comment. Grassman is not convinced about the link between genius and insanity, summarizing the literature as follows "According to these diverging views, genius is claimed by some as an etiologically important factor [for psychosis], rejected by others with equal determination (Grassmann, 1896, p. 972)." In his discussion of the possible familial link between crime and insanity, Grassman raises concerns that the link could be environmental and not hereditary in origin: It is now considered beyond doubt that the misery of the social situation, infirmity, and alcoholism on the part of the progenitors, abuse of the mother and similar circumstances primarily cause a criminal tendency to develop, and that these circumstances can give rise to mental illness in the offspring to a greater degree than the criminal nature of the parents (Grassmann, 1896, p. 973).
He makes the same point with respect to alcoholism: This material disposition of descendants is heightened by a moral one, in that the parents' drunkenness, through bad example, inadequate education, and other factors, becomes a risk for the children to more easily be afflicted by mental disturbances (Grassmann, 1896, p. 974).
He is skeptical that all cases of suicide reflect a hereditary risk for insanity because "… there are numerous cases where the motive for the deed is so clearly recognizable and so outside the sphere of what is pathological (Grassmann, 1896, p. 973)." He concludes that "Only in those cases where the tendency to suicide repeats itself in several generations can this be recognized as a sign of mental abnormality and thus pathologically hereditary (Grassmann, 1896, p. 973)." He ends this section with two methodological points. First, he notes that in studying one potential disorder in ascendants of the insane, the occurrence of other disorders is often ignored-a problem we would now call that of accounting for comorbidity.
Second, he raises concern about the lack of control data. After noting that he had suggested that a range of conditions in ascendants predispose to insanity in their descendants, … for the time being, this thesis is not yet elevated to the status of an incontrovertible fact. In any case, however, a decisive objection must be made to the idea that this question is suitable for being decided and proven by statistics. For the diseases mentioned above are so widespread that the statistician must necessarily find them numerously in the ascendants of the mentally ill. Only if it could be proved that these diseases are actually much more common among the ancestors of the mentally ill than in the ascendants of the mentally healthy would this statistical research have any proving power (Grassmann, 1896, p. 976).
It is surprising that Grassmann does not cite the first controlled study of the pattern of hereditary burden in the insane by Jenny Koller (Kendler & Klee, 2020;Koller, 1895) published a year before Grassmann's review.
4.1 | Chapter 2-Section 1-"So-called" the laws of heredity Rather, it emerges empirically that [cases of illness] … can appear at various points in the descendant series, although it is most clearly and reliably demonstrable in the first of the following generations, but also when skipping over to a later one. In the latter case, the hereditary transmission may have taken a detour via a collateral line, or it may appear suddenly in the later generation (Grassmann, 1896, pp. 976-7).
His typology, quite similar to that adapted by other late 19th authors, considers three major forms we outlined above: direct, atavistic and collateral (or indirect) each of which may be similar (like transmits like) or dissimilar-wherein the disorders, although etiologically related, are clinically distinct in ascendants and descendants. He also mentions but rejects the rarer form of "homochromous heredity" requiring the onset of illness to be similar in affected relatives. He here makes the important observation that "… in general, pathological inheritance follows similar modalities to physiological inheritance (Grassmann, 1896, p. 977)." These basic concepts can be combined and modified in many ways, but a uniform explanatory theory remains out of reach.
The attempts to derive a certain rule within the observed individual cases are extraordinarily numerous and varied.
But it must be admitted that the "laws of heredity" established in this endeavor still represent rules with very many exceptions, both in the normal and in the pathological field of heredity. It is understandable that most of the underlying observations relate to the phenomena which come to light in direct heredity, since these cases not only far outweigh in number, but atavistic and collateral inheritance puts much greater obstacles in the way of investigation, partly due to the further temporal distance of the material to be used, partly due to the circumstance that the influences of heredity on the later generations are in themselves much weaker and more blurred than on the first inheriting generation (Grassmann, 1896, p. 977). Grassmann starts this chapter by outlining the key question to be addressed: "What is transmitted by heredity from one generation to the next? (Grassmann, 1896, p. 982)." He has a ready answer: In the field of pathology, with regard to the transmission of psychoses, the experience is certain that fully developed diseases are not inherited, but as a rule only a disposition to mental abnormalities, or to diseases of the nervous system in general: the so-called psychopathic disposition (Grassmann, 1896 p. 982).
But what exactly is this disposition? He begins at a global, psychological level which he argues is generally accepted: This concerns the indications of a state of mental enfeeblement, in which … not only the functional balance of unstable individuals who tend to disturbances and are incapable of correcting them, instead the entire neuropsychic predisposition of the descendants is displaced. The result is a notable discrepancy between the meagerness of the irritants which target the mind, and their effect on it (Grassmann, 1896, p. 983).
However, that is where the consensus ends: … greater differences [among authors] emerge as soon as the attempt is made to more precisely define the abovementioned symptoms of the neuropathic disposition by means of ideas about their pathological-anatomical bases (Grassmann, 1896, p. 983).
What follows is a review of the leading theories of the biological nature of the hereditary diathesis to insanity circa 1895. One summary is that the field has consoled itself "… with hypotheses of 'fine nutritional disturbances, of changes in the molecular mechanism,' without getting any closer to the matter (Grassmann, 1896, p. 983)." Another investigator seeks the impact of "… heredity in 'congenital ganglion dispositions, namely as an individual disposition of the entire nervous system or also of the cerebrum alone, to certain forms of vibration, which become relevant as soon as a related stimulus responds to them (Grassmann, 1896, p. 983).' Others focus on 'certain abnormal conditions of the blood circulation and the metabolism,' others on a nutritional disorder, which passes through the elements of procreation from the parents to the children. p. 983." Grassmann singles out for more detailed review the views of Meynert who argues that genetic effects on risk for mental illness largely result from "anatomical incongruity between the vascular system and the organs it supplies, primarily the brain (Grassmann, 1896, p. 984)." Grassman concludes that very little is firmly known about how the so-called neuropathic predisposition actually acts from a biological perspective.
Grassman then reviews what nowadays we would call the "penetrance" of the hereditary predisposition for insanity. One viewpoint, seen prominently among the French is that "… insanity always represents an illness on a hereditary basis and the importance of all other etiological factors is accorded only a secondary role (Grassmann, 1896, pp. 986-987)." This view has not yet gained general acceptance. On the contrary, others maintain that there is also an acquired, partly congenital psychopathic disposition, which is not based on heredity, but appears as a consequence of certain influences, which only becomes effective in the later course of germ and embryo development. All harmful effects that already affect the fetus intra-uterine are listed as such moments, for example, traumas and illnesses of the mother during pregnancy, especially febrile forms of illness and those which severely damage the mother's nutrition. On the part of the fetus, inflammation of the brain and its surroundings, hydrocephalus, bone diseases. The harmful effects can also only set in during the act of birth (long duration and operative termination of the same). Or the acquisition of the disposition takes place later through illnesses of a certain kind, for example, skull trauma, inflammatory processes in the interior of the skull, also through rheumatism, gout, alcoholism, or through phthisis [Tuberculosis] (Grassmann, 1896, p. 987).
Of note, Grossmann divided these putative environmental effects into three developmental periods: intrauterine, natal, and postnatal.
Grossmann then reviews "physical predisposition signs" that are Above all, we must remember that a number of the socalled "predisposition signs" occur in people whose mind remains completely intact throughout their lives, so that they do not have the significance of pathognomonic signs. Furthermore, most of the physical predisposition signs are not the storm warnings and precursors of the later onset of psychosis, but themselves are traces and remnants of diseases, some of which have run their course and some of which are still present (Grassmann, 1896, p. 987).
Grossmann reviews in some detail the leading form of physical predisposition signs-various abnormalities of cranial structure before progressing onto the mental signs, noting the diversity of the descriptions: The hereditary stigmata set up in the mental sphere find expression in the manifestations of the so-called Moral expressions are under the influence of a highly developed egoism (Grassmann, 1896, pp. 989-990).

| Chapter 3-Section 2-The development of the hereditary disposition
As elsewhere, Grassmann states the goal of this section right at its beginning: The changes in the somatic and mental regions briefly outlined above indicate the existence of the hereditary predisposition as long as it is present as an undeveloped germ in the affected organism. Let us now follow the further formation and development potential of the pathological predisposition (Grassmann, 1896, p. 989).
Grassman first turns to the appropriate unit of analysis: Even with regard to the symptom complex observed in hereditarily insane people, no agreement has been reached as to whether it should be classified and subordinated to the long-established and well-known disease units of mania, paranoia, feeble-mindedness, melancholia, etc., or whether the symptoms of the disease in hereditarily burdened patients do not possibly assume such a specific character, that a separate disease species, namely "hereditary insanity" should be established (Grassmann, 1896, p. 989).
He notes that the French degeneration theorists specifically advocated for the latter solution, particularly du Saulle (Kendler, 2022; Legrand du Saulle, 1873). Grassmann takes a skeptical position, noting, as he does above, that entirely normal individuals can have such stigmata and that some of the stigmata are residual effects of diseases that are now fully recovered.
He then reviews the degree to which specific psychiatric syndromes "breed true" within families, beginning with a more general observation about human heredity and, interestingly, its application in animal breeding: In the physiological sphere, heredity, as can be seen from the history of the individual families and clans, is generally of the same type, that is, it consists in the reproduction of certain characteristics in the ascendants' offspring. Artificial breeding makes use of the phenomenon of similar inheritance in order to achieve the good qualities of one generation of animals in the subsequent younger generation (Grassmann, 1896, p. 993).
Of all the mental syndromes thought to run true within families, consistent with many prior 19th authors, Grassmann emphasizes suicide, but then cites a minority opinion from the several authors claiming to "show all possible forms of mental disorders in the descent of suicides (Grassmann, 1896, p. 993)." He also questions whether multiple cases of suicide within a family should automatically be assumed to result from heredity: If suicide recurs in a number of generations of the same family, one cannot immediately speak of heredity of the same kind, because the suicide of earlier members of a family is an event which, because of the deep affect it evokes, leaves an extraordinary impulse for imitation (Grassmann, 1896, p. 994).
He notes other authors who claim particular specificity for the cross-generational transmission of puerperal psychoses, alcoholism and epilepsy, then typically considered a "mental" disease.
He summarizes, with approval, prior views that homogeneity of familial transmission of particular forms of insanity is most likely when two conditions are met: (1) … heredity is the main cause of the mental disorder, while other causes are absent, or at least are of demonstrably minor importance… (2) … the form of the mental disorder of the ascendant is as simple and pure as possible, corresponding to the typical, known forms… (Grassmann, 1896 p. 995).
But Grassmann then states that in his view of the accumulating literature, homogeneity of transmission of psychiatric illness is the exception, not the rule: … transference of the same type [in families] is not the rule in psychoses. On the contrary, in the past few decades that view has been supported most securely by clinical experience and has therefore become the prevailing one, which represents the idea of an equivalence between mental and nervous diseases, so far as hereditary comes into consideration. This is the doctrine of polymorphism, or hereditary transformation, names which denote… that not only do the mental forms of disease represent one another as equivalents in hereditary reproduction, but also that the diseases of the rest of the nervous system can enter the chain of inheritance as effective links, that is, mental and nervous diseases arise from a common root… (Grassmann, 1896, pp. 995-6).
This view is similar to that postulated by French degeneration theorists as Grassmann makes clear. The idea that the sphere of influence of heredity is extended significantly, was particularly energetically emphasized by Moreau, Morel, Esquirol, Legrand du Saulle, who have presented polymorphism as the most important law of pathological transferability (Grassmann, 1896, p. 996).
Grassman proceeds to review the theoretical substratum of degeneration theory-the neuropathic constitution-which is considered to form the basis of the "neuropathic family" of syndromes. He correctly notes that this approach was also adopted by key German neuropsychiatrists in the later 19th century, including Mobius, Schüle, and Krafft-Ebbing. He quotes Schüle as advocating for the existence of hereditary transformation in the broadest sense, stating that "not only the pronounced mental disorders are inherited, but also nervous, mental and brain diseases, in a mutual relationship of mutual replacement, mutual ability to transition to one another in the descendant series" (Grassmann, 1896, p. 997). … in the great majority of cases heredity produces the mental disease and determines its form, but in a smaller number of external circumstances (e.g., pregnancy, intoxications), they gain a considerable influence on the form (Grassmann, 1896, p. 998).
This suggests a two factor model of transmission of the forms of psychiatric illness-one resulting from heredity and a second from "external" (e.g., environmental) risk factors. Citing the same author, Grassmann suggests two specific patterns of cross-generational transmission. First, he finds a broad pattern of transmission across what we would today term mood disorders: "Mania, melancholia, and cyclothymia randomly replace each other in inheritance (Grassmann, 1896, p. 998)." (At this time, the clinical syndromes of mania and melancholia closely resembled their modern constructs [Kendler, 2020a[Kendler, , 2020b). Second, he observed no cross-transmission between Verrücktheit-broadly nonaffective psychoses in the late 19th century (see Kendler, 2018 for more details)-and mania or melancholia: "Insanity (Verrücktheit) never gives rise to simple mania or melancholy, nor vice versa, while insanity (Verrücktheit), when pure, becomes insanity (Verrücktheit) again (Grassmann, 1896, p. 998)."

| Chapter 3-Section 3-About the tendency to degeneration
Grassmann devotes six pages to reviewing the theory of degeneration as proposed especially by Morel in his famous 1857 volume "Treatise on the physical, intellectual, and moral degenerations of the human species" (Morel, 1857). His detailed attention to this work is an index of the importance of this theory's impact on psychiatric genetics within German psychiatry in the 1890s. As is the case throughout this work, Grassmann is ambivalent about this theory, feeling it has merits (e.g., "no doubt that Morel's views are justified to a certain extent…" [Grassmann, 1896[Grassmann, , p. 1000), but also recognizes its limitations. He again reviews Meynert's objections (see above) and also quotes from subsequent German empirical asylum based work which showed that, "by far the largest part of those with a hereditary predisposition did not have the signs of the original predisposition to the disease (Grassmann, 1896(Grassmann, , p. 1001)" as predicted by Morel's theory. He cites another study showing that many affected descendants of the insane had quite mild forms of mental illness, not the severe syndromes leading to idiocy and sterility as predicted by Morel.

| Chapter 3-Section 4-Critical remarks on the statistics of the heredity of the psychoses
In this lengthy section, Grassmann reviews the extensive literature about rates of "hereditary predisposition (HP)" in insane patients. He argues that the standard way in which this question is operationalized ("How often does heredity come into consideration as an etiological factor in mental illnesses? [Grassmann, 1896[Grassmann, , p. 1004]") is "too general." He justifies his concerns by listing 37 rates of HP from a wide selection of European authors, noting that they range from 4 to 90%.
He cites two major reasons for this wide variation. The first is the kinds of heredity considered (e.g., direct, atavistic and/or collateral) which impacts on the relatives included in the calculations. The second is widely varying definitions of "mental illness" that are employed.
He particularly notes the very wide expansion of disorders considered by the degeneration theorists which he concludes "accounts for the greatest differences in figures (Grassmann, 1896(Grassmann, , p. 1012." He then cites data on the rates of HP for different kinds of severe mental illness, almost all of which was collected in the latter half of the 19th century: melancholia, mania, paranoia, progressive paresis and epilepsy. The figures vary widely in each type but nonetheless, Grassmann feels the data is sufficiently different to argue that … it should be clear that it is far more correct not to base research on the hereditary nature of psychoses on "mental diseases" as an indivisible whole, but on the individual manifestations of this… (Grassmann, 1896(Grassmann, , p. 1009. In further text, Grassman reviews in the impact, on rates of HP in asylum patients of sex (higher in females than males) and marital status (higher in single than married or widowed). He emphasizes the importance of considering "indirect" hereditary by cited results showing the substantial number of patients with grandparents, aunts/ uncles and siblings affected with mental illness.
Grassman then reviews several methodological issues with the assessment of HP. First, individual informants, either patients or their close relatives, will, because of the shame involved, sometimes conceal information about mental illness in relatives. Second, the informants will often not know of illness that actually occurred, especially in more distant relatives. Third, it is particularly hard to "go back to the history of several previous generations (Grassmann, 1896(Grassmann, , p. 1011)" as even if information is found, it is often hard to interpret because of the changes in views of mental illness over time. Fourth, the assessment of milder syndromes in relatives (e.g., eccentricities, simple depressions, common criminality), can be especially problematic because mental disturbances that are to be used statistically are very close to the bounds of what is normal, which means that there is a great deal of room for subjective judgment… (Grassmann, 1896(Grassmann, , p. 1001.
He again criticizes those who assume that all forms of psychopathology in ascendants must indicate an HP, noting the potential   (Grassmann, 1896(Grassmann, , p. 1017.
Note that he here accepts Weissman's theory of the primacy of the germ-line.
Second, he writes "The nature of the neuro-and psychopathic predisposition has not yet been clarified (Grassmann, 1896(Grassmann, , p. 1017." He posits, vaguely, an important role of "preconditions of a chemical and anatomical nature (Grassmann, 1896(Grassmann, , p. 1017." Third, he rejects the theory of heredity as a universal and primary cause of insanity, specifically suggesting that the importance of an "acquired psychopathic constitution, is confirmed by clinical experience (Grassmann, 1896(Grassmann, , p. 1017." He adds that stressors could play a key role in the etiology of psychosis: it is not sufficient for the assumption of a hereditary mental disorder if burdening factors can be found in the relevant ascendants. It should be considered whether causal moments do not exist in the life of the descendent, which by themselves could produce a psychosis (Grassmann, 1896(Grassmann, , p. 1018.
Fourth, he rejects two key tenants of the degeneration theory initially stating that "The so-called predisposition signs cannot claim the importance of pathognomonic symptoms (Grassmann, 1896)." He then adds that Morel's theory of degeneracy has been proven by more recent research to be too far-reaching, since the conditions for the recovery of infected generations occur far more frequently than Morel assumed (Grassmann, 1896(Grassmann, , p. 1018.
Fifth, he returns to the problem of the very heterogeneous estimates for "hereditary burden." Research must become more rigorous because the current … statistical question is far too general and indefinite if it is based on a concept such as "mental illness" which is too comprehensive. Only an exact differentiation of this based on the criteria of the clinical groups can lead to more consistent results (Grassmann, 1896(Grassmann, , p. 1088.
That is, the data needs to move away from global (and highly variable) definitions of all mental illness (and then some, for example, eccentricity, genius, etc.) and focus on specific disorders with defined "criteria." Furthermore, to be more generalizable, it would be important to study patients not only in asylums, but also those "…in private care, which … make up a very large proportion of all mental patients (Grassmann, 1896(Grassmann, , p. 1088." His final comment might, from our perspective of over 125 year later, be considered prophetic: A closer look at the current theory of the hereditary nature of the psychoses shows that heredity, which probably represents the most important etiological factor in the pathogenesis of mental illness, will also remain a very difficult problem for scientific research for a long time to come (Grassmann, 1896(Grassmann, , pp. 1018.

| DISCUSSION
As noted above, for those interested in the history of psychiatric genetics, Grassmann's scholarly and detailed review of the field, pub- Second, he points out a number of central methodological concerns in the field. There remains uncertainty about the kind of heredity to be studied. He criticizes those who focus solely on "direct" heredity (e.g., parent-offspring transmission), pointing out how much useful data is thereby missed. He is impatient with the lack of standardization about which disorders in relatives should constitute evidence for an HP. He favors moving away from a global focus on insanity in hereditary studies and the study of the then well recognized "clinical groups" such as mania, melancholia and Verrücktheit.
He points out that psychiatric genetic studies should expand beyond the patients seen in asylums. He enumerates the practical problems in obtaining accurate histories of mental illness in relatives and cites the latest research pointing out the biological implausibility of the IAC. He succinctly summarizes the debates about the "boundary" of those disorders of hereditary relevant to for risk to insanity, suggesting that eccentricities should likely be included, and perhaps some neurologic syndromes but probably not genius. He is interested in the genetically influenced premorbid features of those who are at high risk for later insanity.
Third, Grassmann gives substantial attention to degeneration theory, which testifies to its continued impact on the thinking about hereditary transmission of mental illness outside of France at the close of the 19th century. His views on the value of the theory are nuanced.
At times, he makes favorable comments about its importance and validity. However, utilizing empirical studies from the German literature which were contrary to the predictions of the theory, he ends up with a broadly critical conclusion that it is "too far-reaching" in its predictions.
Fourth, Grassman does not assume that all familial transmission of mental illness must arise from heritable influences. At several points in his essay, he raises the possibility of psychological effects or "imitation" as additional sources of family resemblance.
Fifth, Grassman discusses at considerable length the evidence in favor of both homogeneous and heterogeneous transmission of forms of mental illness in families. He provides evidence for both, noting that suicide and mood disorders often display homogenous familial transmission, but agrees with most prior workers that, on average, heterogenous transmission is more common (Kendler, 2021a).
Sixth, at risk of writing "Whiggish" history, it is hard to avoid interpreting Grassmann's suggestion that Verrücktheit in parents almost never produces mood disorders in their offspring and viceversa as anticipating current debates about the genetic relationship between affective disorders and schizophrenia.
Finally, it is also of historical interest to note methodological concerns he does not raise. He accepts, as do virtually all other workers in the 19th century, that the unit of study for heredity is the patient, not their relatives. At this time period, relatives were only studied in so far as they inform upon the HP of the patient. Only post-Mendel did the study of relatives take center stage as investigators tried to uncover Mendelian ratios in close relatives, especially siblings. While Grossmann mentions the concern about base rates of illness, he does not formally call for a case-control study of HP as was published a year earlier by Koller working in Zurich (Koller, 1895).
Several years ago, prior to our first reading of Grassmann's essay, one of us (KSK) reviewed the literature on psychiatric genetics in 48 representative texts, published from 1780 to 1910 (Kendler, 2021a). The major conclusions of this article were all congruent with Grossmann's overview. That two reviews of a similar historical literature conducted 125 years apart, one contemporaneous and one from a considerable historical distance, produced similar findings increases our confidence in the validity of their conclusions. They both demonstrate that the methodological issues arising from the attempts to incorporate Mendel's work into psychiatric genetics in the 20th century can only be fully understood by viewing them in historical context of the prior work in the field done over the 19th century.

AUTHOR CONTRIBUTIONS
The review of this article and the first draft was developed by Kenneth S. Kendler on the basis of the translation of this article performed by Astrid Klee. Astrid Klee researched and wrote the biographical material on Grassmann. Both authors reviewed and revised the first draft.

ACKNOWLEDGMENTS
Translations from the German were performed by AK with the assistance of KSK. Eric Engstrom PhD provided advice and key references for this project.