Janusz Rybakowski: Emil Kraepelin's dichotomy of “endogenous psychoses” in historical perspective


          In my essay, titled “120th Anniversary of the Kraepelinian Dichotomy of Psychiatric Disorders,” published in Current Psychiatry Research (2019), I concluded: “One hundred and twenty years of the presence of Kraepelinian dichotomy of psychiatric disorders has exerted an enormous impact on psychiatric diagnosis and treatment. It can be stated that, as of 2019, this great idea has been still partly valid.”

          In order to generate an exchange on the current status of the controversy about Kraepelin’s “dichotomy” in the following relevant findings in different areas of research are presented.

          In the 6th edition of his textbook, published in 1899, Emil Kraepelin proposed pooling the numerous clinical syndromes to be subsumed under endogenous psychoses into two diseases (clinical diagnoses), one he referred to as “manic-depressive insanity,” today referred to as “bipolar disorder,” and the other he referred as “dementia praecox” that was to be called “schizophrenia” (Kraepelin, 1899)

          In 1933, an American psychiatrist, Joseph Kasanin, coined a term of “schizoaffective psychosis” for describing a clinical phenomenon occupying a space between two dichotomously parted entities mentioned above (Kasanin 1933). In the 21st century Keshavan, Morris, Sweeney et al. (2011) devised the Schizo-Bipolar Scale and showed that the majority of cases had ratings close to prototypic schizophrenia or bipolar disorder, however, a large group (45% of cases) fell on the continuum between these two prototypes.

          Nowadays, dichotomous dopaminergic theory of schizophrenia postulates an increase of dopaminergic function in subcortical areas underlying positive (psychotic) symptoms and a decrease of this function in cortical areas connected with negative (deficit) symptoms. (Breier, Su, Saunders et al. 1997; Slifstein, van de Giessen, Van Snellenberg et al. 2015). Dichotomous dopaminergic theory of bipolar disorder postulates an increase of dopaminergic function in mania and a decrease in depression. The dichotomous glutamatergic theory of major psychiatric disorder suggests a hypoactivity of this system in schizophrenia and hyperactivity in depression.  An abnormality of glutamatergic neurotransmission was postulated in schizophrenia in the mid-1990s as the NMDA receptor hypofunction (Olney and Farber 1995). The concept of an increased NMDA activity in depression arose after showing a rapid antidepressant effect of the infusion of ketamine, an NMDA antagonist (Zarate, Singh, Carlson et al. 2006). In our recent study, we demonstrated that ketamine augmentation rapidly improves depression scores in inpatients with treatment-resistant bipolar depression (Rybakowski, Permoda-Osip and Bartkowska-Sniatkowska 2017).

          Recent genetic studies may speak both for and against the Kraepelinian dichotomy. Much research suggests a genetic overlap between schizophrenia and bipolar disorder. The results of the genome-wide association study (GWAS) from the International Schizophrenia Consortium (2009) confirmed a substantial overlap of common polygenic variation between these two illnesses. The comparison of the genetic risk underlying schizophrenia and bipolar disorder was made by Ruderfer, Fanous, Ripke et al. (2014). Apart from evidencing common genes for these two conditions, a specific polygenic risk score was createdfor each of these two conditions.

          The therapeutic effect of typical antipsychotics, antidepressants and classic mood stabilizers in schizophrenia and mood disorders may speak in favor of Kraepelinian dichotomy. Antipsychotic drugs are the mainstay for the acute and long-term treatment of schizophrenia. All of them have also been efficacious for the treatment of mania. However, in bipolar disorder, so-called typical antipsychotics (e.g., haloperidol) can precipitate the occurrence of a depressive episode and do not prevent the affective recurrences. Whereas in the process of introducing to psychiatric therapy the so-called atypical antipsychotics such as clozapine, olanzapine, quetiapine, aripiprazole or risperidone, it has been noted that they possess mood-stabilizing properties. The first such observation about clozapine was made by Zarate, Tohen, Banov et al. (1995).  All atypical antipsychotic drugs exert both acute and prophylactic antimanic activity and some (e.g., quetiapine) also antidepressant activity  (Rybakowski 2018). Therefore, the use of the atypical antipsychotic drugs in the acute treatment and prophylaxis of bipolar mood disorder can provide evidence against Kraepelinian dichotomy.           

          On the other hand, the therapeutic activity of lithium in bipolar disorder and not in schizophrenia can make the argument for Kraepelinian dichotomy.Among bipolar patients, there is a group called “excellent lithium responders” in which a maintenance lithium monotherapy can make the illness not existing (Grof 1999) which may point to a precise therapeutic specificity of lithium in such patients. The percentage of this group amounts to 1/3 of bipolar patients (Rybakowski, Chłopocka-Woźniak and Suwalska 2001) and their clinical characteristics may resemble a classical description of Kraepelinian manisch-depressives irresein with a moderate number of the episodes and complete remission of symptoms between the episodes. On the other hand, lithium does not possess antipsychotic activity and its prophylactic efficacy has been negatively correlated with a feature of cognitive disorganization, connected with a predisposition to psychosis (Dembinska-Krajewska,  Kliwicki, Chlopocka-Wozniak and Rybakowski 2012). Also, in recent GWAS research, the polygenic score for schizophrenia was inversely correlated with lithium treatment response (International Consortium on Lithium Genetics [ConLi+Gen] 2018).

          Anticonvulsants valproate and carbamazepine exert significant antimanic and prophylactic effect in bipolar disorder but not antipsychotic activity in schizophrenia. The anticonvulsant lamotrigine exerts a significant antidepressant and prophylactic activity in bipolar disorder. However, the drug does not act therapeutically in mania and does not exert antipsychotic activity in schizophrenia (Rybakowski 2018). Therefore, in addition to lithium, anticonvulsant mood stabilizers can support the Kraepelinian dichotomy.

          TheKraepelinian dichotomy can also be considered from the perspective of prenatal infections and immunologic insults. It was demonstrated that maternal influenza had been associated with schizophrenia in their offspring (Brown and Derkits 2010). The study of Canetta, Bao, Co et al. (2014) showed that maternal serological influenza exposure was related to a significant five-fold greater risk of bipolar disorder with psychotic features suggesting that, among offspring, maternal influenza may increase the risk of psychosis, rather than schizophrenia per se. Other prenatal infections (Toxoplasma gondii or herpes simplex virus type 2) may have an association with an increased risk for schizophrenia while such a connection with bipolar disorder is doubtful (Brown 2015).      

          According to the Kraepelinian term dementia praecox, a degree of cognitive impairment can differentiate schizophrenia and bipolar disorder. Schizophrenia is characterized by broad global cognitive impairment that precedes the onset of the disease.

          Using the Wisconsin Card Sorting Test for assessing cognitive efficiency, we demonstrated that the performance on this test of patients with bipolar disorder is worse than healthy controls but significantly better than patients with schizophrenia (Rybakowski, Borkowska, Skibinska and Hauser 2006). In another study, we showed that in “excellent lithium responders,” even with long duration of bipolar illness, the performance on cognitive tests was not different than that of healthy control subjects (Rybakowski and Suwalska 2010).

          The similarities and differences between schizophrenia and bipolar disorders can also be conceptualized within the framework of the neurodevelopmental pathogenesis of psychiatric disorders. Premorbid adjustment of schizophrenia patients is significantly worse than that of control subjects while such impairment in bipolar patients has not been shown (Rietschel, Georgi, Schmael et al. 2009). Distinctive for schizophrenia can also be obstetric complications resulting in hypoxic damage to the hippocampus. Among other environmental factors influencing neurodevelopment, urbanicity has been associated with an increased incidence of schizophrenia but not bipolar disorder (Kelly, O'Callaghan, Waddington et al. 2010; Pedersen and Mortensen 2006). Migration has also been an important risk factor for schizophrenia while there is no conclusive evidence for its role in a bipolar disorder (Cantor-Graae and Selten 2005; Swinnen and Selten 2007).

          As a result of more impaired development, most schizophrenia patients at the first onset of illness show neuroanatomical changes (lateral ventricular enlargement and gray matter abnormalities) and cognitive deficits that is usually not the case in patients with bipolar disorder (Demjaha, MacCabe and Murray 2012).



Breier A, Su TP, Saunders R, Carson RE, Kolachana BS, de Bartolomeis A, Weinberger DR, Weisenfeld N, Malhotra AK, Eckelman WC, Pickar D. Schizophrenia is associated with elevated amphetamine-induced synaptic dopamine concentrations: evidence from a novel positron emission tomography method. Proc Natl Acad Sci U S A. 1997; 94(6):2569-74.

Brown AS, Derkits EJ. Prenatal infection and schizophrenia: a review of epidemiologic and translational studies. Am J Psychiatry 2010; 167:261-80.

Brown AS. The Kraepelinian dichotomy from the perspective of prenatal infections and immunologic insults. Schizophr Bull 2015; 41:786-91.

Canetta SE, Bao Y, Co MD, Ennis FA, Cruz J, Terajima M, Shen L, Kellendonk C, Schaefer CA, Brown AS. Serological documentation of maternal influenza exposure and bipolar disorder in adult offspring. Am J Psychiatry 2014; 171: 557-563.

Cantor-Graae E, Selten JP. Schizophrenia and migration: a meta-analysis and review. Am J Psychiatry 2005; 162:12-24.

Dembinska-Krajewka D, Kliwicki S, Chlopocka-Wozniak M, Rybakowski J. The effectiveness of prophylactic use of lithium in bipolar disorder and schizotypal traits (in Polish). Pharmacother Psychiatry Neurol 2012; 28:153-8.

Demjaha A, MacCabe JH, Murray RM. How genes and environmental factors determine the different neurodevelopmental trajectories of schizophrenia and bipolar disorder. Schizophr Bull 2012; 38:209-14.

Grof P. Excellent lithium responders: people whose lives have been changed by lithium prophylaxis. In: Birch NJ, Gallicchio VS, Becker RW, editors. Lithium: 50 Years of psychopharmacology: new perspectives in biomedical and clinical research. Cheshire, CT: Weidner, 1999; 36–51.

International Consortium on Lithium Genetics (ConLi+Gen), Amare AT, Schubert KO, Hou L, Clark SR, Papiol S et al. Association of polygenic score for schizophrenia and HLA antigen and inflammation genes with response to lithium in bipolar affective disorder: a genome-wide association study. JAMA Psychiatry 2018; 75:65-74.

International Schizophrenia Consortium, Purcell SM, Wray NR Stone JL, Visscher PM, O'Donovan MC, Sullivan PF, Sklar P. Common polygenic variation contributes to risk of schizophrenia and bipolar disorder. Nature. 2009; 460:748–52.

Kasanin J. The acute schizoaffective psychoses. Am J Psychiatry 1933; 90: 97-126.

Kelly BD, O'Callaghan E, Waddington JL, Feeney L, Browne S, Scully PJ, Clarke M, Quinn JF, McTigue O, Morgan MG, Kinsella A, Larkin C. Schizophrenia and the city: A review of literature and prospective study of psychosis and urbanicity in Ireland. Schizophr Res 2010; 116:75-89.

Keshavan MS, Morris DW, Sweeney JA, Pearlson G, Thaker G, Seidman LJ, Eack SM, Tamminga C. A dimensional approach to the psychosis spectrum between bipolar disorder and schizophrenia: the Schizo-Bipolar Scale. Schizophr Res. 2011; 133(1-3):250-4.

Kraepelin E. Psychiatrie. Ein Lehrbuch für Studierende und Ärzte. 6 Auflage. Barth, Leipzig, 1899.

Olney JW, Farber NB. Glutamate receptor dysfunction and schizophrenia. Arch Gen Psychiatry 1995; 52:998-1007.

Pedersen CB, Mortensen PB. Urbanicity during upbringing and bipolar affective disorders in Denmark. Bipolar Disord 2006; 8:242-47.

Rietschel M, Georgi A, Schmael C, Schirmbeck F, Strohmaier J, Boesshenz KV, Schwarz M, Nöthen MM, Schulze TG. Premorbid adjustment: a phenotype highlighting a distinction rather than an overlap between schizophrenia and bipolar disorder. Schizophr Res 2009; 110:33-9.

Ruderfer DM, Fanous AH, Ripke S, McQuillin A, Amdur RL; Schizophrenia Working Group of the Psychiatric Genomics Consortium; Bipolar Disorder Working Group of the Psychiatric Genomics Consortium; Cross-Disorder Working Group of the Psychiatric Genomics Consortium, Gejman PV, O'Donovan MC, Andreassen OA, Djurovic S, Hultman CM, Kelsoe JR, Jamain S, Landén M, Leboyer M, Nimgaonkar V, Nurnberger J, Smoller JW, Craddock N, Corvin A, Sullivan PF, Holmans P, Sklar P, Kendler KS. Polygenic dissection of diagnosis and clinical dimensions of bipolar disorder and schizophrenia. Mol Psychiatry. 2014; 19:1017-24.

Rybakowski JK, Chłopocka-Woźniak M, Suwalska A. The prophylactic effect of long-term lithium administration in bipolar patients entering lithium treatment in the 1970s and 1980s. Bipolar Disord 2001;3 :63-7.

Rybakowski JK, Borkowska A, Skibinska M, Hauser J. Illness-specific association of val66met BDNF polymorphism with performance on Wisconsin Card Sorting Test in bipolar mood disorder. Mol Psychiatry 2006; 11:122-24.

Rybakowski JK, Suwalska A. Excellent lithium responders have normal cognitive functions and plasma BDNF levels. Int J Neuropsychopharmacol  2010; 13:617-22.

Rybakowski JK, Permoda-Osip A, Bartkowska-Sniatkowska A. Ketamine augmentation rapidly improves depression scores in inpatients with treatment-resistant bipolar depression. Int J Psychiatry Clinical Pract 2017; 21:99-103.

Rybakowski JK. Meaningful aspects of the term 'mood stabilizer'. Bipolar Disord 2018; 20:391-2.

Rybakowski JK. 120th Anniversary of the Kraepelinian Dichotomy of Psychiatric Disorders. Curr Psychiatry Rep. 2019; 21(8):65.

Slifstein M, van de Giessen E, Van Snellenberg J, Thompson JL, Narendran R, Gil R, Hackett E, Girgis R, Ojeil N, Moore H, D'Souza D, Malison RT, Huang Y, Lim K, Nabulsi N, Carson RE, Lieberman JA, Abi-Dargham A. Deficits in prefrontal cortical and extrastriatal dopamine release in schizophrenia: a positron emission tomographic functional magnetic resonance imaging study. JAMA Psychiatry 2015; 72:316-24.

Swinnen SG, Selten JP. Mood disorders and migration: meta-analysis. Br J Psychiatry 2007; 190:6-10.

Zarate CA, Tohen M, Banov MD, Weiss MK, Cole JO. Is clozapine a mood stabilizer? J Clin Psychiatry 1995; 56:108-12.

Zarate CA Jr, Singh JB, Carlson PJ, Brutsche NE, Ameli R, Luckenbaugh DA, Charney DS, Manji HK. A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry 2006; 63:856-64.


November 21, 2019