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Kahlbaum, Hecker, and Kraepelin and the Transition From Psychiatric Symptom Complexes to Empirical Disease Forms


Kahlbaum, Hecker, and Kraepelin and the Transition From Psychiatric Symptom Complexes to Empirical Disease Forms


Kenneth S. Kendler, M.D., Eric J. Engstrom, Ph.D.

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 protodisease 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 characteristicsymptoms,was paradigmaticfor them.Their hope was that a similar progression of medical understanding would evolve for the othermajor 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 tohelp 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.

Am J Psychiatry 2017; 174:102–109; doi: 10.1176/appi.ajp.2016.16030375

Kraepelin’s articulation of two major forms of psychosis—dementia praecox and manic-depressive insanity—in the 5th and 6th editions of his textbook (1, 2), published in 1896 and 1899, represented a foundational event for modern psychiatry. Differences in course and outcome comprised the critical basis for Kraepelin’s position. The goal of this essay is to trace historically the origin of Kraepelin’s diagnostic approach. This takes us back to two earlier figures in German psychiatry, Karl Kahlbaum (1828–1899) and his protégé Ewald Hecker (1843–1909) (3), and their writings from the early 1860s through the 1890s (4). Kraepelin acknowledged the influence of both men on his clinical methodology (5, 6). Kahlbaum’s work in particular has been singled out as the “first modern clinical classification” (7), and the years leading up to the publication of Kraepelin’s influential textbook have been described as “Kahlbaum’s Era” (8). Healy has recently suggested that contemporary psychiatry is more indebted to Kahlbaum than to Kraepelin and hence our neo-Kraepelinian era is, in fact, a neo-Kahlbaumian one (9). The essential position of Kahlbaum and Hecker was that the psychiatric diagnoses of mid-19th century German psychiatry were nothing but “symptom complexes.”

As Kahlbaum wrote,

…the various forms in which mental illness has been known since antiquity, and is still known today, cannot be considered as different species in their own right but only as symptomclusters which can appear in the course of different disorders. (10, p. 236)

Hecker restates this position forcibly:

…the commonly accepted names for psychiatric illnesses, i.e., melancholia, mania, insanity, confusion and dementia are completely unsuitable and insufficient, because these names do not designate true disease forms but temporary conditions. (11, pp. 349–350)

Kahlbaum had been the first to reach this conclusion after a comprehensive analysis of past nosologies in his seminal monograph of 1863 on the classification of psychiatric diseases (12). The sheer number of nosologies led him not only to chide psychiatrists for their relentless addiction to novel diagnostic systems, but also to differentiate between 1) strictly symptom-oriented classifications that allowed for numerous, but often hopelessly contradictory, forms and 2) classifications that grouped symptoms into symptom complexes. None of the bygone “splitters” or “lumpers” who had developed such classifications had, however, succeeded in laying a “stable, scientific foundation” (12, p. 139) for psychiatry. And when it came to actually diagnosing their patients, Kahlbaum argued that psychiatry’s many “rationalistic,” “non-empirical,” or “armchair” classifications had left physicians in the lurch. In fact, Kahlbaum’s look back at earlier nosologies was a story of psychiatrists often blinded by their own “rationalistic” preconceptions and in need of empirical evidence to overcome those biases.
Kahlbaum and Hecker repeatedly drew on parallels from general medicine in making their nosologic position clear. Kahlbaum noted that the earlier psychiatric symptom complexes were analogous to “dropsy,” which was “a syndrome common to a number of [disease] conditions” (13, p. 175). Hecker wrote that if these psychiatric syndromes were “transferred to somatic medicine, they would correspond to a classification of headache, chest pain, abdominal pain, etc.” (11, p. 350). In a later passage, Hecker described “cough” as being analogous to the psychiatric classifications of mania and melancholia (11, p. 352).

The problem with the use of these symptom complexes, they argued, was that, because of their great heterogeneity, they prevented physicians fromgaining useful insights into etiology, prognosis, and treatment. Each case became its own study. Generalizations to provide clinically useful information were impossible. Turning again to general medicine, Hecker noted the critical difference between the clinician who diagnosed a headache—providing little helpful information—and one who diagnosed a headache due to typhoid fever, where the diagnosis now carried important information about prognosis and treatment. In addition to relying on examples from general medicine, Kahlbaum and Hecker also utilized their clinical observations (14), pointing to the proven clinical “fact” that melancholy and mania had quite variable outcomes and could end in either cure or dementia.

If Kahlbaum was dissatisfied with the confusion that plagued traditional psychiatric terminology, he was equally discontented with the findings of pathological anatomy. Mockingly, he tookhis neuropathological colleagues to task for suggesting that the largely unsatisfactory andconfusing results of psychiatric autopsies were simply attributable to ignorance about cerebral anatomy or to the fact that they simply had not “cut up and rummaged around in enough psychiatric corpses” (12, p. 60). The only tangible result of postmortemstudieswas that none of the existing nosologies could be correlated with necroscopic evidence in anythingmore than the most general way. These failings were, however, not largely attributable to pathoanatomic methods, but were due rather to the inadequate “descriptions and demarcations of diseases” with which neuropathologists had to work (12, p. 173).

Skepticism about pathoanatomic research was no less forcefully expressed by Hecker. In his programmatic 1871 article onclinical psychiatry,he noted that the promise of neuropathology, particularly as articulated by earlier major figures such as Wilhelm Griesinger (1817–1868) in his dictum that mental illness was brain disease, had not yet yielded much fruit. Hecker wrote that

…the subtle anatomy and physiology of the brain are still in a dismal state and…the pathological anatomy of the psychoses up to now has offered us extremely few hard facts. (11, p. 351)

Hecker saw no need to wait for pathological anatomy and even argued that doing so represented a kind of “passive resistance” that involved clinging to old nomenclature simply because pathological anatomy had not delivered on its promises yet (15, p. 211). Kahlbaum and Hecker wanted to break this resistance and make the formation of clinical forms the immediate and pressing goal of a clinically oriented psychiatric research program. Ratherthancallingfor largerandmore refinedpostmortemstudies, Hecker laid the failure of this approach back on theinadequacies of psychiatric nosology. He argued against the then-dominant view that the way forward for diagnosis was through advances in brain-based research and that once the etiology had been discovered through neuropathology, this would lead to a definitive resolution of the diagnostic questions. Rather,Hecker turned this position on its head, arguing that psychiatric neuropathology would advance only once it had moved beyond traditional “diagnoses” that were, in fact, mere symptom complexes. With evident exasperation, he wrote,
No wonder we find in “mania” at times this and at times that change…. in the brain. Would it be any different if wewere to trace the anatomo-pathological substrate of “abdominal pain”? (11, p. 351)
Here again, using examples drawn from general medicine, Hecker countered the argument that etiologic research had to precede good psychiatric diagnoses. Many ofwhat he tellingly termed the “empirically based disease forms” of his day (his examples included Graves’ disease and typhoid fever, the bacterial cause of which was not discovered until 1880) had unknown etiology. Psychiatry, he argued, was putting the cart before the horse by jumping enthusiastically into etiologic research before the development of true clinical syndromes. Turning to general medicine, he noted that
Long before the changes of the organs could be demonstrated with the knife in hand [pathology], certain disease forms were propounded according to empirical, clinical observation….Why, then, in psychiatry do we want to wait until we have found an anatomo-pathological basis instead of nominating… disease forms on the basis of detailed and precise clinical observation? (11, pp. 351–352)
In support of this key point, Hecker appealed to Rudolf Virchow (1821–1902)—a leading light of late 19th century scientific German medicine. In defending the practice in general medicine of first defining empirical disease forms and then searching for their etiology, Virchow wrote,
…I believe that there exists in every other natural science thesame method of initially assigning certain things to an empirical group and giving it a name while reserving the search after the true origin… for a later time. (15, p. 210; 16, p. 39)

So what was this method of “detailed and empirical clinical observation” that Hecker advocated and how could it be applied to psychiatric illness?

Hebegan by stating whatitwasnot. It did not involve using a “predefined classification principle.” Nor did it derive different forms of mental illness from the presence or absence of a single symptom. This was the classical deductive approach used in early botany and zoology, where classification proceeded by key divisions based on single characteristics, such as tree versus shrub, flowers versus no flowers, warmversus cold-blooded, etc. (17). Hecker and Kahlbaum argued that the major psychiatric syndromes of their day relied on a similarly simplistic a priori distinction. That is, the formula was something like “excited/grandiose + insane = mania” and “retarded/morose + insane = melancholia.” In this fashion, earlier nosologists had developed certain “rules” governing symptom aggregation and selection. But what they lacked, and what Kahlbaum and Hecker sought to add, was a “rule of the course” that would be used to break up symptom complexes and constitute new and specific disease entities (12, p. 152).
Expressing their mission in general terms, this method required that psychiatrists “keep an eye on the whole course of the illness when observing patients” (11, p. 352). Hecker then advocated, with a bit more precision, taking broad syndromes and, on the basis of such careful observation, splitting them up into more specific disease forms.
Heused theexample of infectious diseases,where“clinical disease forms” such as typhoid and cholera were separated out from the “symptom constellation” of “fever.” How was this separation accomplished? He focused initially on time course. It was rarely the occurrence of fever alone that was definitive diagnostically. Rather it was “its course, its sequential rise and fall and its exchange with fever-free time” (11, p. 354). Of additional importance were the associated symptoms andsigns, such as specific kinds of rash or diarrhea.

Hecker’s case was strengthened by the existence of a uniquely psychiatric example of his proposed method for the delineation of specific disease forms. He wrote,

The only real disease form which has gained entry into psychiatry provides the best evidence for this [proposed process]:…progressive paralysis of the insane [aka general paresis of the insane (GPI)]. (11, p. 353)

What differentiated GPI from other less specific psychiatric syndromes was both “a peculiar and special course” and a set of relatively unique symptoms and signs. He wrote,

It is not the single symptoms of grandiose delusion of the paralysis which allow us to propound this disease form, but the grouping of these symptoms into a clinical picture and the peculiar course which the disease runs as a whole. (11, p. 353)

It is hard to exaggerate the importance of this example of GPI in the conceptual framework that Kahlbaum and Hecker developed. We will now turn to how they applied the lessons of GPI (i.e., a distinct course accompanied by characteristic clinical features) to the articulation of what theywould claim as three distinct “true diseases”: hebephrenia, catatonia, and cyclic insanity.


While first proposed by Kahlbaum, the concept of hebephrenia was fully articulated by Hecker in his famous 1871 article (18). In describing hebephrenia, Hecker drew on the example of GPI.Heckerwrotethat akeydistinctive featureof the course of GPI, as noted originally byWestphal, was the “early onset of a quickly advancing dementing process among the psychiatric signs of the paresis.” He went on to write,

Kahlbaum was the first to point out … that this markedly striking feature is part of another disease, which has not much else in common with paresis: namely hebephrenia. (18, p. 93).

Hebephrenia stood out, Heckerwent on to argue, “due to its typical course and range of specific symptoms” (18, p. 93), the same language he used for describing the kinds of features that made GPI so clearly a distinct diagnostic entity. In particular, Hecker repeatedly commented on the characteristic thought disorder that occurred in hebephrenia and was sufficiently distinctive that “veryoften one canmake thediagnosis just from the hebephrenic’s letters” (18,p. 99). Inparticular, he notedthat
they often were “almost entirely consisting of shallow, meaningless phrases” (19,p. 235). Several quotes fromthe speechand letters of Hecker’s cases are presented in Figure 1.
Hecker’s use of these letters is important for reasons that relate specifically to his aim of tracking the early development of hebephrenia in his patients. The letters were so
important that Hecker’s clinical casematerial was confined to patients in whose files such letters existed. He valued the letters—citing them verbatim and liberally—for the
“objective” and “unbiased” preclinical evidence that they yielded. Because of hebephrenia’s rapid progression to dementia, alienists had usually seen only the later stages of the illness, after the “actual illness” had run its course and the patients had already arrived “mentally crippled” in the asylum (20, p. 396). Patient letters opened a window on to the course of hebephrenia.
Hecker’s and Kahlbaum’s understanding of hebephrenia was facilitated by the fact that, unlikemost alienists, theywere well placedto studypsychiatric disorders inadolescents.Their asylum in Görlitz was a private sanatorium that served a wealthy, international clientele and that had acquired a reputation as an institution specializing in the treatment of young patients (21). As a part of the asylum’s therapeutic regime, Kahlbaum developed a pädagogicum to enable “specialized
medical observation and treatment” for a large and rapidly growing number of young patients. The pädagogicum employed a special staff of teachers who were “embedded organically and methodologically” into daily asylum life and who, through “patient, methodical, pedagogical influence,” aimed to correct their young patients’ “failed up-bringing” (12, p. 6; 22; 23).

Kraepelin’s university clinic had no pädagogicum. Whereas Kahlbaum and Hecker had used hebephrenia’s course to establish it as a distinct nosological entity, Kraepelin
believed that they had found only a specific subtype of mild dementia characteristic of younger, upper-class patients. Drawing on the workof his student Leon Daraszkiewicz (24), Kraepelin therefore admitted more severe forms of hebephrenia that terminated in severe dementia and were less influenced by external factors (6, 25).
The influence on Kraepelin of Hecker’s work on hebephrenia can be clearly illustrated by this short quote from Kraepelin’s first systematic description of dementia praecox in the 4th edition of his textbook:

The first precise, and in many ways exemplary, description of certain forms of dementia praecox was given by Hecker in 1871. (26, p. 442)

Indeed, Kraepelin explicitly emphasized the deep affinity between Hecker’s hebephrenia and dementia praecox. At the same time, however, he believed thatHecker’s categorywas too narrowly focused on pubescence and needed to be expanded to include Daraszkiewicz’s findings. It was precisely to accommodate this expanded understanding of hebephrenia that Kraepelin proposed theterm“dementia praecox” (27,p. 1016), a term used previouslybyGerman and French psychiatrists, such
as Heinrich Schüle and Bénédict Morel (28–30).


Kahlbaum began his famous 1874 monograph on catatonia (31) by commenting on the role of “organic signs” in the diagnosis of psychiatric syndromes—were they non specificor specific and therefore of critical diagnostic importance? He answered this question by giving a brief history of the thencurrent thinking about the etiology of GPI:

At first, the paralytic component was regarded merely as a complication … but it gradually became clear that the psychiatric disorders involved were present more specifically in association with the pathognomonic paralytic phenomena typical only of this disease and that there was a close connection between the progress of the psychic phenomena and the somatic components. (31, p. 7)

He then began his description of what he called catatonia and its close relationship with the “striking” cataleptic states and “waxen” flexibility. He wrote, These interesting somatic features are as unique in the diagnosis of this particular illness as are the somatic components of general paralysis of the insane. (31, p. 9) But it was not only the presence of characteristic clinical symptoms that made catatonia resemble GPI:
In some aspects, such as the clinical course marked by the passage through various phases of distinct mental states and the significant association with muscular disorders, the one is analogous to the other. (31, p. 9)

Later in the monograph, he again focused on course and its ability to help define diseases from more heterogeneous symptom complexes. After describing the rich clinical symptoms seen in his catatonic cases, he wrote, If one observes, however, how these combinations repeat themselves frequently and how, when they do appear, the
combination occurs in a certain sequence which recurs again and again in different patients, the conclusion must be drawn that all these occurrences have a common etiology and only represent progressive transformations with the same basic
process. (31, pp. 26-27)
He summarized his views as follows:
In this newly defined group of disorders, similar to the general paresis of the insane (GPI) … clinical changes in the locomotor apparatus form the main and typical features of the disease; in addition, each disease (GPI and this disease) exhibits manifold patterns of symptoms. (31, p. 27)
Kraepelin’s uptake of Kahlbaum’s views on catatonia was slow. In 1879, five years after publication of Catatonia, alienists in the Munich asylum where Kraepelin worked had
yet to diagnose a single case of the disorder (6). Furthermore, Kraepelin’s early mentors and colleagues thought little of Kahlbaum’s work (6, 32, 33). And more than a decade later, in 1890, Kraepelin still openly resisted Kahlbaum’s interpretation of catatonic symptoms, hoping to demonstrate that they were characteristic of a specific, volitional disorder as opposed to Kahlbaum’s view of catatonia as a motility psychosis (6, 34). Nevertheless, Kraepelin ultimately adopted and popularized Kahlbaum’s concept of catatonia in his textbook, partially in the 4th edition of 1893 and completely
by the 5th edition of 1896 (35). Like Kahlbaum and Hecker, Kraepelin also focused on the disorder’s course and outcome in isolating its characteristic symptoms. But his observations yielded a fundamentally different clinical picture of catatonia. Whereas Kahlbaum’s catatonia was a so-called “total” mental disorder that progressed from mania and melancholy through insanity to dementia, Kraepelin dispensed with this sequence and posited a much more negative outcome. And whereas Kahlbaum described catatonia as amotor-neural disorder and distinguished it from GPI chiefly on the basis of its cataleptic symptoms, Kraepelin pointed to patients’ waxy flexibility in placing greater emphasis on a volitional rather than a neuropathological etiology. (Crucially, itwas thepoor outcome of catatonia that brought him to associate itwith dementia praecox. In his years of clinical experience, Kraepelin claimed to have never encountered a case with obviously catatonic symptoms that did not culminate indementia.Furthermore, the “frequency of catatonic signs” in more typical cases of dementia praecox strongly suggested that both were manifestations of the same morbid process [26, p. 454].)


We can also learn about how Kahlbaum and Hecker used information about course and symptoms to move toward empirical disease forms by analyzing Kahlbaum’s discussion of cyklisches Irresein, or “cyclic insanity,” published in 1882 (36). The fundamental contrast he made was between the occurrence of the symptoms of mania and melancholia in cyclic insanity versus in what he called “typical insanity.” According to his definition, cyclic or circular insanity was a form of illness, in the course of which melancholia and mania, two apparently contrasting states, are observed to follow each other. This succession repeats quite often and more or less regularly with intervening intervals of true or at least apparent mental health. (36, p. 83)
Typical insanity,bycontrast,was thenamehegavetoaunitary psychosis as articulated by Wilhelm Griesinger and Heinrich Neumann. As understood at this time, the basic idea was that there was only one true form of insanity and all the individual major syndromeswere just transitory manifestations of that one disorder. Focusing initially on mania, Kahlbaum noted that the course was quite different from that seen in cyclic insanity:

In typical insanity, the manic phase after having reached a peak without remission can change into a kind of insanity with confusion that may eventually reach a stage of idiocy or so-called terminal dementia. (36, p. 84)

He noted this apparent discrepancy in the course and outcome of these affective syndromes as follows:
It is often found that the course of typical insanity, once the peak of mania or rage has passed, leads to weakness and eventually to complete decline of mental power. In comparison to this course, it is remarkable that there are alsomany cases of illness in which melancholia and mania can be very intense, yet end in remission without mental decline. (36, p. 84)
Kahlbaum then asked the key question “Are the melancholia and mania in cyclic insanity to be considered the same as the melancholia and mania in typical insanity?” (36, p. 84). He noted the general similarity of the clinical forms but then made the trenchant observation that “a closer look at their detailed features reveals substantial differences.” Note that he began by articulating differences in the course of these syndromes, but nowhe was moving to the second criterion that he wanted to use in shifting fromsymptomcomplexes to empirical disease forms, that is, to differences in symptoms and signs. He began with melancholia. In typical insanity, the initial melancholic phase was often of a “vague character” and represented “the sultriness before the thunderstorm” (36, p. 84) of the emerging psychosis. By contrast, in the melancholia of cyclic insanity, the mood symptoms were much more distinct, often accompanied by self-accusations, and closely resembled the full melancholic syndrome seen “in disorders in which only melancholia occurs” (what we would now call unipolar major depression). Kahlbaum then noted that “the difference inmania between cyclic and typical insanity is even sharper” (36, p. 84). To follow his argument,weneedtonote that Kahlbaum proposed aversion of faculty psychology that divided the mind into three major functions: feeling, intellect, and volition. In typical insanity, the manic syndromewas not restricted to the domain of feeling, but it “quickly reaches such a degree and extent that all the major mental functions are disturbed” (36, p. 84)—that is, both intellect and volition—and becomes a “pervasive derangement.” By contrast, in the mania of cyclic insanity, the disturbance was restricted only to the domain of feeling. They have an irrepressible cheerfulness, without real delusions, but only exaggerations of self-esteem and of other emotions. Such patients can explain everything they say and do in an understandable and even seemingly reasonable way. (36, p. 84) Using mania in a way that is unfamiliar to us (as an agitated, grandiose psychosis affecting all aspects of mental functioning—mood, intellect, and volition), Kahlbaum summarized his conclusion as follows: The stage of exaltation in the cyclic insanity group is not an actual mania involving exaltation of all mental functions, only of the emotions. In contrast, in typical insanity leading to terminal idiocy, the exaltation is a true mania. (36, p. 87) So we began with the two classical symptom complexes of mania and melancholia. Kahlbaum then argued that they could occur in two different disease courses—as part of typical insanity and cyclic insanity. He then observed the associated difference in course with the former often leading to deterioration and the latter to multiple recurrences but without dementia. Then he focused in on the clinical symptoms, noting, on closer observation, a number of important differences. And finally, in keeping with his taxonomic agenda, Kahlbaum named these two forms “vesania typica circularis” and “cyclothymia.” In the 6th edition of his textbook, published in 1899, Kraepelin claimed that he had found no clinical evidence to support Kahlbaum’s distinction between “vesania typica circularis” and “cyclothymia” (37, vol. 2, pp. 416–417). Kraepelin arrived at this conclusion not least because he was no longer beholden to Kahlbaum’s ‘typical insanity’ and the notion of unitary psychosis that underpinned it. But he also drew on his own clinical observations, citing cases involving severe manic episodes that did not result in cognitive deterioration. As Kraepelin’s category of manic-depressive illness developed, however, it was clearly not the allencompassing “total” disorder of Kahlbaum’s typical insanity that culminated in dementia but, instead, much closer
to his cyclical affective disorder. Critically, he adopted Kahlbaum’s key concept that patients with manic-depressive insanity did not develop dementia even in the setting of chronic symptoms. This was clearly expressed in the final edition of his textbook:
… the attacks of manic-depressive insanity with the delimitation attempted here never lead to profound dementia, not even when they continue through life almost without interruption. Usually all morbid manifestations completely disappear; but where that is exceptionally not the case, only a rather slight, peculiar weakness develops. (38, p. 3) Interestingly, Kraepelin expanded Kahlbaum’s concept of cyclothymia to include cases with single manic or depressive episodes. That, however, is another story.

The influential nosology for major psychiatric disorders developed by Kraepelin in the 1890s and still of substantial importance to our field did not arise de novo. Rather, Kraepelin’s work was strongly influenced by and indeed largely basedon concepts developed in the preceding decades by Kahlbaum and Hecker. The field has been slow to recognize this interdependence, in large part because neither Kahlbaum nor Hecker was widely known in their own day. Neither had university appointments (a critical mark of professional status at this time), and both spent almost all of their
careers in private asylums. This dependence of Kraepelin on his predecessors is well captured in a key early review of his work by the then rising star of American psychiatry, Adolf Meyer. He wrote, A very stirring turn in psychiatry has come lately from Kraepelin, who took a stand foreshadowed by Kahlbaum, but never demonstrated with such consistency before. With the fifth edition of his textbook, the time had come to break away from the resigned symptomatic attitude [as] the pride of the clinician demanded disease entities. (39, p. 651) Kahlbaum, Hecker, and Kraepelin shared a commitment to a clinical research agenda for psychiatry in which the first and foremost task was to utilize the methods of clinical assessment and follow-up to help define disease forms. The conceptual framework for this approach was laid down by Kahlbaum and Hecker, and it was further developed by Kraepelin. Indeed, a major focus of Kraepelin’s clinical research career involved developing more fully the nosologic paradigm proposed by his older colleagues (4). Working in high-prestige academic centers with a large flow of patients and sufficient staff to assist him, and using his famous system of “patient cards” (Zählkarten) (40, 41), Kraepelin was able to
expand considerably the clinical program of research along the lines first articulated by Kahlbaum and Hecker (4). It is important to emphasize that, in the decades around
1900,Kraepelinwasnotworkinginisolation.Majorpsychiatric nosologieswere proposed by his approximate contemporaries, including Kraft-Ebbing (42, 43) and especially the neuropsychiatrist Carl Wernicke (44–47).While Wernicke’s work led to an alternative diagnostic tradition within German psychiatry, represented by Karl Kleist and Karl Leonhard (48), its contemporary influence on psychiatric nosology has been minor
compared with Kraepelin’s. The nearly world-wide acceptance of Kraepelin’s nosologic
system arose from a range of factors, including his prominent status in the field of psychiatry, the broadly recognized quality and subsequent wide influence of his textbook, and the ability of this new paradigm to convey a sense of excitement and scientific promise compared with the existing syndromal typologies, which were seen as old and increasingly scientifically sterile (49). These three men also shared a deep skepticism for the “brain-based” neuropathological paradigm of psychiatric research dominant in most European academic centers during the latter half of the 19th century. However, this skepticism never prevented Kraepelin, as a professor in both Heidelberg and Munich, from recruiting and supporting the research of leading neuropathologists, including Franz Nissl, Alois Alzheimer, and Korbinian Brodmann (50, 51). During the critical period from about 1860 to 1900, Kahlbaum, Hecker, and Kraepelin were together responsible for a paradigm shift in the conceptualization of psychiatric diagnosis. They moved from the symptom-based syndromes popular since the late 18th century (mania, melancholia, dementia, etc.) and from the eclectic range of 19th-century armchair nosologies to what we might call proto-disease entities. In this effort, they were strongly influenced by parallel developments in general medicine, especially the rise of bacterial theories of disease (52) in which different disorders often had distinct symptoms and illness courses. Even more important, their thinking was shaped by the increasing understanding and delineation of the syndrome of GPI. This disorder, with its distinctive course and characteristic
symptoms that were increasingly clearly delineated over this time period (its etiology was not definitively demonstrated until 1913 [53]), was paradigmatic for these three clinical researchers, shaping their approach to the other psychiatric syndromes then populating Europe’s asylums. Put simply, their hope was that—as GPI was shown to have distinct symptoms, a particular course, and eventually a unique etiology—a similar progression of medical understanding would evolve for the other major psychiatric syndromes. This paradigm shift was, however, built on a promise that
has not yet been fulfilled. GPI has proven to be the exception and not the rule among the major psychiatric syndromes. We still do not know whether this “Kahlbaum-Hecker-Kraepelin paradigm”—defining disorders on the basis of distinctive symptoms and course—will produce psychiatric syndromes that are sufficiently homogeneous to yield up their etiologic secrets. Indeed, Kraepelin’s nosology met with vigorous opposition by some psychiatric contemporaries (30, 50, 54). He was particularly criticized for his idiosyncratic use of prognosis as a key to diagnosis…. [noting that] the criterion was logically weak since the course of any illness also depended upon fortuitous conditions, such as the severity of the lesion and host resistance, neither of which could be considered as ‘essential’ aspects of the disease. (4, p. 818)
Our task here is not to prognosticate the future of this paradigm so central to the history of our discipline but to suggest that understanding its historical origins will help us nowand in the future to evaluate its strengths and limitations. Afinal question is whether the sole focus of the Kahlbaum-Hecker-Kraepelin paradigm on clinical research methods restricted the subsequent trajectory of psychiatric nosology. Each of these three clinicians reacted skeptically to the premature claims in late 19th-century Germany that brain science, then largely neuropathology, would soon be capable of solving the problems of psychiatric nosology. Their colleague and competitor Carl Wernicke attempted to develop a psychiatric nosology founded in brain function (44–47), but that effort proved premature and bore limited scientific fruit. Would a more inclusive nosologic vision that included both biological and clinical methods have led to more rapid progress in psychiatric nosology? Such historical counterfactuals (“What would have happened if…?”) are problematic to evaluate given the inherent unpredictability of historical processes. Our view of the recent history of biological psychiatry suggests a nuanced response. Certainly, on their own, the robust claims from biologically oriented researchers that psychiatric nosology could be based on simple neurochemical processes (55, 56) or major Mendelian-like genes (57–59) have proven incorrect. Indeed, reviews as recent as DSM-5 have concluded that the best-replicated findings of biological psychiatry were too nonspecific to be of diagnostic utility (60). What was potentially lost, then, was not a single major biological breakthrough that would illuminate an entire nosologic area, like the discovery of the Treponema. Rather, what may have been missing was an iterative process in which the mutual strengths of the available fallible clinical and biological tools interacted synergistically on nosologic problems. With the increasingly powerful biological tools now available to our field, it may be time to revisit the question of whether and how biological measures can be usefully integrated into clinical approaches to psychiatric nosology like those pioneered by Kahlbaum, Hecker, and Kraepelin.

TABLE 1. Examples of Thought Disorder in the Speech and Letters of Patients With Hebephrenia as Described by Ewald HeckerIn the following, all italics are as in Hecker’s original monograph (19).

Letter from Case IV

Waiting for a long time for a most polite and dear letter from you, or since the times nowadays are not the best ones, I take the liberty to entrust you with a diff erent gesticulating fascicle….Most tormented for a longtime in the asylum by Görlitz I am extremely obliged to claim a yearly wage commencing 1st of the year of 51 cigar boxes, if it does not work out to stay here for such a long time, so I am extremely obliged to comply with your wishes, if it does work out to start anew, then it is going to work out the following day to the extremes in a holiday barn …, etc. Interview with Case V He is asked whether he knows Colonel von S., who had inquired about his well-being and he answers: “Oh, yes, he is my regiment commander in Lötzen.” (I think he is in Königsberg?) “No, he is a retired major from the war—he has 300 Thaler to spend, since those who retire in peacetime have 700 Thaler to spend and those who retire in wartime 300 Thaler.” (How is this possible? It should be exactly the other way round.) “Yes, you see, money was made of iron then, which is not worth that much, but at least they can enjoy themselves.”

Letter from Case V

Dear father! Because of what you wrote in your last letter or explained lately regarding the birthday, which I am hopefully planning to celebrate in 4 months’ time at your place provisionally very advantageously to go through with, I still cannot decide to make the parts of the watch case to get the surprise fi nished by 13. December and to put it in perfection regarding its content. Regarding the French way of my letter I feel pressurized to take into consideration the gold coin amounting to 5 Thaler (20 Sgr) and to make the fortune accessible to myself with some Latin or unpedagogic dervish matters and translations or notes.

From the Virginia Institute of Psychiatric and Behavioral Genetics and the
Departments of Psychiatry and Human and Molecular Genetics, Virginia
Commonwealth University School of Medicine, Richmond; the Max
Planck Institute for Psychiatry, Munich; and the Department of History,
Humboldt University, Berlin.
Address correspondence to Dr. Kendler (kenneth.kendler@vcuhealth.
Supported in part by theMax Planck Institute for Psychiatry (Dr. Engstrom).
The authors report no financial relationships with commercial interests.
Received March 30, 2016; revisions received May 23 and May 31, 2016;
accepted June 13, 2016; published online Aug. 13, 2016.
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