Marcelo Cetkovich-Bakmas’ Comment  
“Phenomenology could be the Master Key”
Donald F. Klein’s comment on Thomas A. Ban: The Wernicke-Kleist-Leonhard Tradition with Special Reference to Mania, Melancholia and Manic-Depressive Psychosis

             The discussion about the “nature” of psychiatric disorders is still an open debate. As pointed out by Kendler, some diagnostic concepts in psychiatry are “progressive” meaning that they add understanding and predictability (Kendler 2016). That is the case for Kleist and Leonhard´s splitting of affective disorders into a Unipolar and Bipolar concept. Could this also be the case for Klein´s Pharmacologic Dissection of anxiety disorders into GAD and Panic Attack (Klein 1964)? Later he was able to relate Panic with Agoraphobia and to keep apart Social phobia (Mannuzza et al. 1990). It is clear that Klein’s contributions were the base to build what we can call the Differentiated Psychopathology of Anxiety Disorders (Barlow 2013). On the other hand, he was also involved in differentiated psychopathology of affective disorders with his studies about “endogenomorphic” depression (Klein 1974; Stewart et al. 1980).  Within this framework it is hard to understand why the WKL nosological distinctions bothers him so much.

Psychoses are extremely complex disorders; several psychopathological domains are affected with divergent trajectories and manifold manifestations across patients (Tandon, Nasrallah and Keshavan 2009; Addington and Piskulic 2010; Azzone et al. 1990; van Os and Kapur 2009).

What Dr. Klein considers confirmatory anecdotes are decades of clinical wisdom -- quiet and careful observation of signs, symptoms, outcome and prognosis of hundreds of patients made by Wernicke, Kleist and Leonhard´s school, as clearly shown in Dr. Ban´s post.

Its heuristic value is recognized by a compact group of psychiatric practitioners and researchers across the world. Notwithstanding, others consider this approach too complex to understand and hard to be learned.

Psychiatry must take note of other disciplines, like physics or astronomy, where complex questions are not avoided in the name of utility. Sophisticated and highly expensive experiments are carried out in order to access further knowledge, no matter how painful the process may be. CERN´s Hadron Collider Experiment is a good example.

Psychiatry has moved in an opposite direction. In order to give answers to complex issues, like the causes and mechanisms of conditions resulting from malfunction of the most complex organ known by mankind, modern psychopathology struggles to make simpler that which is highly complex. Current genetic researchers compete each other not to find what makes bipolar disorder and schizophrenia different things; instead they dive into the wide grey area of commonalities and get lost (Witt et al. 2017; Cross-Disorder Group of the Psychiatric Genomics Consortium 2013; International Schizophrenia Consotrium, 2009; O’Donovan, Craddock and Owen 2009). These studies are all examples of the use of complex molecular techniques to scan poorly defined phenotypes. Huge amounts of money are expended in sophisticated genome-wide scan studies in affective disorders and schizophrenia, but all of them take for granted that both are one single disease, or even worse, that they are not different conditions. Not a single study has considered the possibility that these conditions comprise several different diseases or even clinical forms, something that a more sophisticated clinical assessment than commonly used would detect.

This scenario was challenged by Arnedo et al. (2015). In a controversial study using sophisticated statistical analysis of data from three different genome-wide association studies (GWAS), they demonstrated a complex molecular and clinical architecture combination, supporting the clinical/genotypic heterogeneity of schizophrenia. They were able to dissect eight clusters of combinations of sets of single nucleotide polymorphisms (SNPs) with sets of clinical traits, finding a “hidden” complex architecture not confirmatory of schizophrenia as a single diagnostic category. This paved the way to start stressing the possibility that the genetic complexity is related with phenotypic complexity. Diversity is the base of complexity.

The elimination of schizophrenia´s clinical forms from DSM 5 was not a data driven decision (Tandon 2014). Once again, absence of evidence was equated with evidence of absence, but no modern study seriously addressed this subject.  One frequent argument is lack of stability of clinical forms through time. Karl Leonhard’s advice, at the beginning of his classification, is that clinical forms of psychosis are recognized after years of evolution and that early stages are highly unspecific from the clinical point of view. This is confirmed by modern early intervention in psychosis that showed the low capability of predicting transition to psychosis, as well as the clinical condition in so called “At Risk Mental States” (van Os and Kapur 2009; Tsuang et al. 2013; Fusar-Poli et al. 2017).

 All GWAS studies assume that genetic loading is normally distributed.  The “Genes by Environment” interaction became the master key (van Os, Rutten, and Poulton 2009). Nobody takes in account that both terms of this equation are not constants, but variables in a way that at some point genetic loading factors overcame environmental ones and vice versa; this simple idea was proposed by Leonhard himself in a time when not a single cue pointed towards environmental factors.

Main reason for Kraepelin's dichotomy being “enormously popular” and “crushing” is nothing but simplicity or “clinical utility (validity)” (Kendell and Jablensky 2003). His early 1899 classification, the simplest one, is the one that succeeded, in spite of the fact that Kraepelin himself rejected such an oversimplification in his later writings. Kraepelin's dichotomy provides a useful approach for every day clinical practice, that's a fact, but failed once again as able to define phenotypes for research purposes. Clinical utility of the Kraepelinian dichotomy could be a good argument for a global management tool like the DSM, aimed to help every specialist make a diagnosis in order to implement treatment; it is only simplicity and its utility is what “crashes” other approaches.  It is nothing but a mistake, however, to use this dichotomy to point towards an understanding of neurobiological basis of those disorders. This scenario prompted Tom Insel’s NIMH´s initiative to abandon DSM categories for research and to adopt the Research Domain Criteria Approach (Cuthbert and Insel 2013). Poorly defined phenotypes failed to fill the gap between clinical manifestations and neurobiology. A dimensional approach became the alternative to deal with these inconsistencies (van Os, Rutten, and Poulton 2009; Kaymaz and van Os 2010)

Every taxonomy struggling with the natural world assumes that differences in appearance are the reflection of hidden processes acting through nature, nurture (i.e., environment) or the interaction of both. What nowadays seems evident was uncovered just 150 years ago by Charles Darwin (Costa 2014).

The theoretical underpinning for separating clinical entities regarding their symptom profile, outcome pattern, prognosis and family loading is parsimonious: if the appearance and evolution of a clinical phenomenon are different, most probably they are different things. Ornithologists do not hesitate to separate two species of birds just because of tiny differences.  They know evolution made the difference through genes, environmental factors and time. This is the underlying hypothesis for differentiated psychopathology.

Leonhard's classification proposed that genetic loading (familiality) in psychosis is not normally distributed and proposed that some cases are more influenced by genetic factors and others by environmental ones. Franzek and Beckmann`s 1998 twin study found a higher concordance for non-systematic schizophrenias than for systematic ones (Beckmann, Fritze, and Lanczik 1990; Franzek and Beckmann 1998). Season of birth, a proxy indicator for environmental factors, was also addressed in a study over Leonhard´s own 1,299 patient records. Systematic schizophrenias and cycloid psychosis - where environmental factors were expected to have a bigger role compared with genetic loading - displayed a spring births´ peak. This is in accordance with data that postulates season of birth (Davies et al. 2003; Owen et al. 1989) as an indicator of early gestational insults, like viral infections (Franzek and Beckmann 1992). For these investigators this data supports the idea of etiologically different groups within schizophrenia (Franzek and Beckmann 1996).

Cycloid Psychosis is located in Leonhard´s classification, between affective (“phasic”) psychosis and the two families of schizophrenias. Salvatore et al. (2008) reviewed the evidence supporting the existence of this condition as a separate disorder worth being further investigated. Good prognosis in long term of cycloid psychosis was demonstrated in a four-year follow up study (Beckmann, Fritze, and Lanczik 1990).  Interestingly, the patients in the study were diagnosed as having schizophrenia or schizoaffective disorder when RDC or DSMIII criteria were used.

Validity and reliability of Leonhard´s classification was stressed in a long-term study by Petho´s group, the “Budapest 2000 Study” (Tolna et al. 2001; Petho et al. 2007; Petho et al. 2008) and in a brief cross sectional study by Pfuhlmann et al. (1997).

Not being the mainstream approach in psychosis research, differentiated psychopathology has been addressed by several groups.  Peralta and Cuesta have demonstrated, using stringent statistical analysis of careful longitudinal psychopathological assessments, that endogenous psychoses comprise a group of conditions with different psychopathological profiles, family loading, outcome and prognosis. For example, they demonstrated that, as postulated by Leonhard, family loading was different in the two main groups of schizophrenia, systematic and non-systematic (Peralta et al. 2016), in spite of the fact that their powerful study indicated a reversal of the effect of genetic loading in systematic schizophrenias -- an issue to be addressed in further studies.  The same group demonstrated that catatonic traits are a psychopathological dimension with transdiagnostic properties, something that was proposed by Leonhard himself, who showed that psychomotor traits could be found in cycloid psychosis, systematic schizophrenias and non-systematic schizophrenias, and affective psychosis as well. Peralta and Cuesta also demonstrated in a hierarchical model of psychopathology, that dimensions and categories are not mutually exclusive and their data do not support the idea of psychosis as a single disease entity (Peralta et al. 2017).

If there is not enough data about a psychopharmacological response according to the clinical form, this is due to the fact that the clinical samples were not ordered according to the assumption.  Notwithstanding, in 1959 Christian Astrup observed that the therapeutic response to neuroleptics of Leonhard’s Unsystematic Schizophrenias was better than in the systematic ones (Astrup 1959), a fact later confirmed by the British psychiatrist Frank Fish (1964).

            In his post it is clear that Klein missed the fact that for differentiated psychopathology the objective is, always, to stress the assumption that a different clinical picture, outcome and prognosis are manifestations of still hidden different etiopathogenetic mechanisms. To keep the things apart is presumed as a good strategy for advances in biological research still coming. The importance of differentiated etiology for Leonhard is expressed in the title of his book, “Classification of Endogenous Psychoses and Their Differentiated Etiology” (Leonhard 1999). All the clusters within the classification are organized according to phenomenology and family loading.

            Once again, Kenneth Kendler helps us understand the difficulties Anglo-American and German genetic researchers have had to understand each other based on the different traditions in genetic research: Mendelians from the German side - base for the traditional German categorical approach - and Biometricians - who pave the way for the dimensional approach - on the other side (Kendler 2015).

            In sum: we can´t expect simple answers to complex questions. Differentiated psychopathology as proposed by the WKL school as a hypothesis that is not taken at all into account by modern research. This does not mean that it is false, just further serious research is needed.

            Perhaps the answer could be found by means of Big Data and Machine Learning analysis of big samples of patients, but psychopathological assessment needs to be refined. WKL could be a good guidance for this enterprise.

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April 26, 2018