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 Paul Grof


         I want to thank Paul Grof for his interesting observations about urea and also for sharing with me his correspondence with Jay Amsterdam. I have three remarks:

         First, although there is some similarity in the name, urea and uric acid are different kinds of stuff. Urea, also known as carbamide, is famous for being the first organic compound synthesized from inorganic elements by Friedrich Wöhler in 1828. It is the end product of proteins and other nitrogen substances originating in the so-called ornithine cycle from amino acids: ornithine, citrulline and arginine. On the other hand, uric acid, which is chemically 2,6,8-trioxypurine, is the end product of the metabolism of purine bases coming from food and synthesized de novo from the breakdown of endogenous nucleic acids. Both substances are connected with nitrogen metabolism. However, converting urea into uric acid does not take place in humans.

         Secondly, it is rather unlikely that urea exerts any psychotropic activity and the results described by Grof and Toman (1968) could be due to a placebo effect. The role of placebo in the acute and maintenance treatment of unipolar and bipolar mood disorders has been still insufficiently investigated, as indicated by Jay Amsterdam. Probably this effect could be more pronounced in unipolar than in bipolar mood disorders. Therefore, we are awaiting Jay’s reanalysis of the STAR*D study in this respect.

         Finally, as the eminent lithium researcher, Paul Grof may observe that 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 and John Cade in the mid-20th century. He probably also followed the article by Felber (1987) written on the 100th anniversary of Carl Lange’s book, where the uric acid hypothesis of mood disorders was completely refuted as an example of a false theory that could 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; Salvatore, 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.



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Bartoli F, Crocamo C, Mazza MG, Clerici, M, Carrà G. Uric acid levels in subjects with bipolar disorder: A comparative meta-analysis. J Psychiatr Res 2016;81;133-9.

Chung KH, Huang CC, Lin HC.  Increased risk of gout among patients with bipolar disorder: a nationwide population-based study. Psychiatry Res 2010;180:147-50.

Felber W. Die Lithiumprophylaxe der Depression vor 100 Jahren - ein genialem Irrtum. Fortschr Neurol Psychiatr 1987;55:141-4.

Grof P, Toman M. Prophylactic value of urea in recurrent affective psychoses. Act Nerv Super (Praha) 1968;10: 294-5.

Gubert C, Fries GR, Wollenhaut de Agular B, Rosa AR, Busnello JV, Ribeiro L et al. The P2X7 purinergic receptor as a molecular target in bipolar disorder. Neuropsychiatry Neuropsychol 2013;8:1-7.

Jahangard L, Soroush S, Haghighi M, Ghaleiha A, Bajoghli H, Holsboer-Trachsler E et al. In a double-blind, randomized and placebo-controlled trial, adjuvant allopurinol improved symptoms of mania in in-patients suffering from bipolar disorder. Eur Neuropsychopharmacol 2014;24:1210-21.

Salvadore G, Viale CI, Luckenbaugh DA, Zanatto VC, Portela LV, Souza DO et al., Zarate, C.A. Jr., Machado-Vieira, R. (2010). Increased uric acid levels in drug-naive subjects with bipolar disorder during a first manic episode. Prog Neuropsychopharmacol Biol Psychiatry 2010;34: 19–82.


September 26, 2019