Janusz Rybakowski: 120 years of the Kraepelinian dichotomy of "endogenous psychoses" in historical perspective

Janusz Rybakowski’s reply to Edward Shorter’s comments


        I appreciate very much the comments of Edward Shorter who pointed out several weaknesses of the concept of Kraepelinian dichotomy. I would like to address them successively:                                                                                                                                

1. The unipolar - bipolar distinction of mood disorders.    
Several decades after Kraepelin lumped together bipolar and unipolar mood disorders under the umbrella of manisch-depressives Irresein, other German psychiatrists started to make a differentiation. The precursor of this approach was Karl Kleist who distinguished unipolar (German, einpolig) and bipolar (German, zweipolig) affective disorders. His successor, Karl Leonhard (1995), separated bipolar psychoses (manic-depressive and cycloid) from unipolar psychoses (melancholy, depression, euphoria and mania). However, most important for this distinction were the works of Jules Angst and Carlo Perris, both published in 1966, in which each of them, independently, reported on a different occurrence of mental disorders in the families of patients with unipolar and bipolar affective disorder (Angst 1966; Perris 1966). Since then, the specifier for bipolar disorder has been the occurrence of (hypo)mania, which is reflected in DSM-5. In this classification, bipolar disorder and major depressive disorder constitute separate classes. On the other hand, in recent years, a neo-Kraepelinian approach to mood disorders has emerged. According to it, the most cyclic and recurrent forms of unipolar depression should be included in a bipolar spectrum (Saggese, Lieberman and Goodwin 2006). This was reflected in the second edition of Goodwin-Jamison’s book Manic-Depressive Illness: Bipolar Disorders and Recurrent Depression (Goodwin and Jamison 2007). Incidentally, it should be also mentioned that Jules Angst is a great advocate of a concept of unipolar mania (Angst and Grobler 2015).                  

2. The specificity of psychopharmacology of schizophrenia and mood disorders.
The main psychopharmacological evidence against the Kraepelinian dichotomy emerged following the introduction of the so-called atypical antipsychotic drugs. These drugs, apart from being effective in schizophrenia, possess mood-stabilizing properties, evidenced by preventing affective recurrences (mostly manic) in bipolar disorder (Rybakowski 2018). Some of them, such as quetiapine, lurasidone and cariprazine, also exert, as monotherapy, significant therapeutic activity in bipolar depression.         
However, this broad activity of atypical antipsychotics cannot blight a therapeutic specificity of the first-generation antipsychotics in schizophrenia and other psychotic disorders, and therapeutic efficacy of antidepressants in various kinds of depression (and also anxiety disorders). It has been also demonstrated that the first generation of mood-stabilizing drugs (lithium, carbamazepine, valproates) are therapeutically effective in bipolar disorder and not schizophrenia or other psychotic disorders. As to lithium, with which I have the most experience, we found that its prophylactic efficacy has been negatively correlated with a feature of cognitive disorganization, connected with a predisposition to psychosis (Dembinska-Krajewska, Kliwicki, Chlopocja-Wozniak and Rybakowski 2012). Also, in recent genome-wide association study (GWAS) research, the polygenic score for schizophrenia was inversely correlated with lithium treatment response (International Consortium of Lithium Genetics, Purcell, Wray et al. 2018).      

3. The opposed activity of some neurotransmitters in schizophrenia and mood disorders.
A lot of data suggests that dopaminergic and glutamatergic systems may behave in oppositional ways in various psychiatric disorders. There has been evidence of increased dopaminergic activity in schizophrenia (with dominant psychotic symptoms) and mania, which is reflected in the efficacy of antipsychotic medication, blocking dopaminergic receptors, in these conditions (Breier, Su, Saunders et al. 1997; Ashok, Marques, Jauhar et al. 2017). On the other hand, decreased dopaminergic activity is connected with schizophrenic negative symptoms (Slifstein, van de Giessen, Van Snellenberg et al. 2015), and also postulated in depression (Dailly, Chenu, Renard and Bourin 2004). In schizophrenia, the hypoactivity of the glutamatergic system (decreased activity of NMDA receptors) has been presumed (Olney and Farber 1995). Conversely, in depression, increased activity of the NMDA receptor has been assumed, which can be therapeutically influenced by the administration of ketamine, the NMDA receptor blocker (Zarate et al, 2006). Demonstration of the antidepressant effect of ketamine was one of the most interesting events of psychopharmacology in the 21st century. It can be supposed that such opposing activity of these neurotransmitters can speak in favor of the Kraepelinian dichotomy for schizophrenia and mood disorders.      
4. Overlap and specificity of molecular genetics in schizophrenia and bipolar disorder.
There is a lot of genetic overlap between schizophrenia and bipolar illness. On the clinical level, this was evidenced by the study of Lichtenstein, Yip, Björk et al. (2009).  Searching medical records of more than 2 million nuclear families in Sweden, they showed that first-degree relatives of probands with either schizophrenia or bipolar disorder were at increased risk of both these disorders. However, there were also differences. The specific sets of genes for schizophrenia and bipolar disorder have been identified and established as the polygenic risk scores for schizophrenia and bipolar illness (Ruderfer et al. 2014). Furthermore, a genetic difference between schizophrenia and bipolar illness may lie in the magnitude of the copy number variations (CNV) which are chromosomal micro-duplications or deletions, significantly more common in schizophrenia than in bipolar illness, thus making a meaningful distinction between these two disorders (Green, Rees, Walters et al. 2016).      
        As many psychiatric disorders show significant molecular-genetic overlap, seen mostly in GWAS studies, it was interesting that in a recent large study, no genetic overlap was demonstrated between psychiatric disorders and such neurological disorders as generalized epilepsy, Parkinson's disease, Alzheimer's disease or multiple sclerosis (Brainstorm Consortium, Antilla, Bulik-Sullivan et al. 2018). This could suggest that medical specialization into psychiatry and neurology can have some substantiation. Of course, this finding does not have any relationship to the psychiatric dichotomy suggested by Kraepelin.  

       Therefore, assuming all reservations raised by Edward Shorter, in my opinion the Kraepelinian dichotomy of psychiatric disorders still remains as a significant heuristic, scientific and clinical concept in psychiatry                                                                                                



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May 14, 2020