Saturday, 08.08.2020

Magda Malewska-Kasprzak, Agnieszka Permode-Osip and Janusz K. Rybakowski: Disturbance of the purinergic system in affective disorders and schizophrenia 

 

Janusz Rybakowski’s reply to Hector Warnes’ comments

 

        I want to thank Hector Warnes for his ideas supporting the role of adenosine and nucleotide receptors in the pathogenesis of mood disorders and schizophrenia. To summarize the current evidence concerning this issue, it can be assumed that a deficiency in the adenosine system can be found in both these groups of disorders.

        This year we observe the 120th anniversary of German psychiatrist Emil Kraepelin (1856-1926), acting at that time as the Professor of psychiatry and director of the Psychiatric Clinic of the Heidelberg University, publishing the sixth edition of his textbook on psychiatry. Kraepelin made a fundamental dichotomous distinction of psychiatric disorders based on the course and outcome, the main aspect of which was a cognitive deterioration, delineating the two main groups (Kraepelin 1899). The first, with a chronic course and systematic cognitive deterioration, was called dementia praecox. The second, with the periodic course and a relative lack of cognitive deterioration, was called Manisch-depressives Irresein. Dementia praecox was further conceptualized as "schizophrenia" by Swiss psychiatrist Eugen Bleuler (2011). From the current perspective, Manisch-depressives Irresein is now the closest to the concept of "bipolar mood disorder."

        It is known that Kraepelin himself assumed the possibility of not so definite boundaries between dementia praecox and manisch-depressives Irresein in many patients (Kraepelin 1921). A meaningful contribution to these doubts was a concept of schizoaffective disorder in the 1930s (Kasanin 1933). However, it was not until the turn of 21st century when significant confirmation for an intermediate space between schizophrenia and bipolar disorder was obtained by psychopharmacological and genetic studies. The main pharmacological argument for this is the mood stabilizing properties of the atypical antipsychotic drugs (Rybakowski 2018) while, for the other, a shared genetic make-up of schizophrenia and bipolar disorder (Lichtenstein, Yip, Björk et al. 2009; International Schizophrenia Consortium et al. 2009).

        However, it is interesting to note that the Kraepelinian dichotomy of psychiatric diagnosis has been supported by neurobiological research studying neurotransmitter systems. Presently, there are dichotomous neurotransmitter concepts related to schizophrenia and mood disorders. The bipolar dopaminergic theory in connection with schizophrenia postulates hyperdopaminergia in positive (psychotic) symptoms and hypodopaminergia in negative (deficit) symptoms (Breier, Su, Saunders et al. 1997; Howes, Kambeitz, Kim et al. 2012; Slifstein, van de Giessen, Van Snellenberg et al. 2015). As to bipolar disorder, mania would be connected with increased and depression with decreased dopaminergic activity (Schildkraut 1965; Ashok, Marques, Jauhar et al. 2017). The glutamatergic theory suggests a deficit of glutamatergic mechanisms, especially the N-methyl-D-aspartate (NMDA) receptors, in schizophrenia (Olney and Farber 1995) and an excess in depression. 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).

        As mentioned previously, the purinergic hypothesis postulates a deficit of the adenosine system in both depression and in schizophrenia, showing a relative similarity in this respect in the background of neurobiology in major psychoses. Therefore, it could be supposed that the purinergic hypothesis of psychiatric disorders can contribute to the arguments against the dichotomous Kraepelinian concept of schizophrenia and mood disorders.

 

References:

Ashok AH, Marques TR, Jauhar S, Nour MM, Goodwin GM, Young AH, Howes OD. The dopamine hypothesis of bipolar affective disorder: the state of the art and implications for treatment. Mol Psychiatry 2017;22:666-79.

Bleuler E. Dementia praecox, oder Gruppe der Schizophrenien. Leipzig: Deuticke, 1911.

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 USA 1997;94:2569-74.

Howes OD, Kambeitz J, Kim E, Stahl D, Slifstein M, Abi-Dargham A, Kapur S. The nature of dopamine dysfunction in schizophrenia and what this means for treatment. Arch Gen Psychiatry 2012;69:776-86.

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.

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

Kraepelin E. Einführung in die psychiatrische Klinik. Vierte, völlig umgearbeitete  Leipzig: Barth Verlag, 1921.

Lichtenstein P, Yip BH, Björk C Pawitan Y, Cannon TD, Sullivan PF, Hultman CM. Common genetic determinants of schizophrenia and bipolar disorder in Swedish families: a population-based study. Lancet 2009;373:234–9.

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

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

Schildkraut JJ. The catecholamine hypothesis of affective disorders: a review of supporting evidence. 1965;122:509-22.

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.

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.

 

October 17, 2019