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


Jay Amsterdam and Paul Grof: E-mail interaction


On May 9, 2019, after theposting of Paul Grof’s comments on Malewska-Kasprzak, Permoda-Osip and Rybakowski’s essay, the following e-mail interaction took place (outside of INHN’s website) between Jay Amsterdam and Paul Grof:


Jay Amsterdam to Paul Grof:


Did you ever pursue a follow up or ‘replicative’ study with urea as a mood stabilizer, especially vs. a different ‘placebo’ (like lactose monohydrate)?

There is, of course, another explanation for your interesting finding, which is that urea was actually a ‘placebo’ in your early trials, and that many patients with recurrent depression (that ultimately morphed into bipolar II disorder with increasing years) did better on ‘urea placebo’ vs. a TCA or lithium monotherapy.

In this regard, I previously performed a series of RCTs of randomized, placebo-controlled design in acute and relapse-prevention therapy of bipolar II depression, and these studies seemed to  indicate that recovered bipolar II depressives randomized to (i) continuation antidepressant therapy (i.e., fluoxetine) vs. (ii) lithium or (iii) placebo (i.e., lactose monohydrate or Rice powder) appear to do similarly well on all three therapies (with the antidepressant monotherapy being best, placebo next and lithium last). Go figure …..Just curious about this issue.

My best,



Paul Grof to Jay Amsterdam:


I did not follow - or try to replicate - the urea observation. By 1967 our findings with lithium were so positive that we wanted to focus on exploring who responds so well.


In hindsight, your explanation may be the best one. It would be supported by 2 other studies we did:

1. In stabilizing treatment of frequently recurrent depressions, placebo resulted in longer remissions than maintenance imipramine (public. 1970)

2. In acute antidepressant treatment using intraindividual crossover designs, placebo was better than imipramine in 6 of such patients.


Best wishes



September 19, 2019