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 Edward Shorter's comments


          I want to thank Edward Shorter for his remarks about schizophrenia and its neurobiological background in relation to the purinergic hypothesis. By no means did I want to push a purinergic component of schizophrenia as a major neurochemical basis for this illness or a group of illnesses, as was initially suggested by Eugen Bleuler (1911) and I presume, currently supported by Edward Shorter.

          The purinergic hypothesis (or uric acid hypothesis) of mood disorders was developed as an aftermath of experiments and clinical trials with lithium by Carl Lange in the second part of the 19th century (Lange 1886) and John Cade in the mid-20th century (Cade 1949). However, the uric acid hypothesis of mood disorders was completely refuted by Felber (1987) in his article written at the 100th anniversary of Carl Lange’s book, as an example for a false theory that could nevertheless result in a spectacular clinical achievement. However, in the 21st century, this concept, also in relation to purines, of which uric acid is the end product, again received some merit for bipolar disorder. The concentration of uric acid was demonstrated as increased in bipolar illness and especially in mania (Bartoli, Crocamo, Mazza et al. 2016; Salvadore, Viale, Luckenbaugh et al. 2010). A drug decreasing uric acid concentration, allopurinol, was found to augment antimanic action of mood stabilizers in mania (Akhondzadeh, Milajerdi, Amini and Tehrani-Doost 2006; Jahangard, Soroush, Haghighi et al. 2014). Also, the prevalence of gout was found higher in bipolar illness compared with the general population (Chung, Huang and Lin 2010). Among purinergic receptors playing a pathogenetic role in bipolar disorder, a conspicuous one appeared the P2X7 receptor, connected with the processes of apoptosis, proliferation and releasing pro-inflammatory cytokines as well as with neurotransmission and neuromodulation (Gubert, Fries, Wollenhaut de Agular et al. 2013).Therefore, nowadays a connection between uric acid, the purinergic system and bipolar disorder can no longer be denied.

          As to schizophrenia, a purinergic component could be only inferred from a connection of purines (mainly adenosine) with dopaminergic and glutamatergic systems. The role of these systems in schizophrenia has been amply demonstrated based on psychopharmacology and also the results of molecular-genetic studies. Antipsychotic drugs blocking the dopaminergic system have been a mainstay of schizophrenia treatment. The Nobel prize in 2000 was awarded to recently deceased Arvid Carlsson for his studies on the dopaminergic system, including the first evidence of the dopaminergic mechanism of antipsychotic drugs (Carlsson and Lindquist 1963). The glutamatergic concept of schizophrenia postulated a deficiency of NMDA (N-methyl-D-aspartate) receptors (Olney and Farber 1995). However, its therapeutic implications pertain only to some efficacy of inhibitors of glycine receptors (a part of NMDA receptors) as augmentation of antipsychotic drugs in the treatment of negative symptoms (Balu 2016).

          On the other hand, the glutamatergic concept of schizophrenia was supported at the beginning of 21st century by molecular-genetic studies showing a connection between a predisposition to schizophrenia and polymorphism of numerous genes of the glutamatergic system (Carter 2006). Also, a variety of genes connected with the glutamatergic system were found in the biggest genome-wide association study (GWAS) of schizophrenia to date, elucidating 108 schizophrenia-associated genetic loci. Among them, the dopaminergic D2 receptor gene was also identified and connected with the action of antipsychotic drugs (Schizophrenia Working Group of the Psychiatric Genomics Consortium 2014). Nevertheless, a connection of the purinergic system with schizophrenia, although suggestive based on the association of this system with dopaminergic and glutamatergic mechanisms, can be much weaker than with bipolar disorder.



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October 3, 2019