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

Paul Grof’s comments


            Professor Rybakowski and his colleagues published an interesting review pointing out the possible role of the purinergic system in the genesis and treatment of affective disorders (Malewska-Kasprzak, Permoda-Osip and Rybakowski 2018). In fact, uric acid and lithium urate played an essential role already in the introduction of lithium into the treatment of recurrent depressions during the 19th (Lange 1896) and manic-depressive illness in the 20th century (Cade 1949)  

            After a hiatus of five decades, new evidence has now emerged about a possible role of uric acid in the pathogenesis and management of bipolar disorders. I will add our own minor observations about urea to this interesting review. The possible connection with professor Rybakowski's report is that in humans urea converts into uric acid.

            In the early 1960s, I explored some possible stabilizations of patients with frequently recurrent depressions.  To reduce the high individual variability that exists in their clinical course, I used intraindividual comparisons in the design:  each patient served, over time, as her/his comparison while receiving during each remission an antidepressant (imipramine), or placebo or no treatment; the sequence of these treatments was determined randomly; and  imipramine and placebo were prepared in identical looking capsules in our Institute's pharmacy.

            When we were evaluating the results, to our great surprise some patients had by far the longest free intervals while taking a placebo. Naturally, while trying to explain this puzzling, unexpected observation, we had to explore the nature of our placebo.  It turned out that our hospital pharmacy had some extra supply of urea and considered it a pharmacologically inert substance. Without advising us, they filled the placebo capsules they provided for the experiment with urea.

            We published the unexpected clinical observation hoping that someone might offer some explanation (Grof and Toman 1968). However, none arrived.

            Mogens Schou became aware of our report, as he always followed the literature about manic-depressive illness very carefully. He then asked me to pursue this observation further.  By that time, however, we already treated several hundred bipolar patients successfully with lithium. So, I was much more interested in investigating who are the bipolar patients responding so remarkably to lithium - the question I was naïvely hoping to answer promptly – rather than starting to search for uncertain answers to the use of urea.

            I should add that further long-term follow-up of some of these patients with recurrent depressions turned out that they actually suffered from bipolar disorders.  Their course started with recurrent depressions and we did not know what would transpire in their future.




Cade JF. Lithium salts in the treatment of psychotic excitement. Medical Journal of Australia 1938; 36: 349-52.

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

Lange C. Periodische Depressionszustande und ihre Pathogenesis. Hamburg and Leipzig: Leopold Voss; 1896.

Malewska-Kasprzak M, Permoda-Osip A, Rybakowski J.  Disturbances of the purinergic system in affective disorders and schizophrenia. Dec. 13, 2018.


May 9, 2019