David Janowsky: Cholinergic muscarinic mechanisms in depression and mania 

Samuel Gerson’s comments on collating document until Edward Shorter’s comment

        I first wish to state that this thread, starting with the contribution of David Janowsky and down through the other contributors, is a valuable addition to the broad implications of this topic. 

        I wish to use my contribution to this thread by dealing with Tacrine as a take off point for a completely different aspect that these studies bring into view.

        I reported on our work with Tacrine and had the opportunity to follow its path from discovery and synthesis of the compound to its demise. It is these events that I think should also be considered as a serious concern in the introduction of new psychopharmacologic entities.  As I mentioned, we studied this compound in the pharmacology department in Melbourne and reported that it had significant stimulant, alerting and analeptic properties.  Later we also found that it had anti-deliriant and anti-hallucinogenic effects on Ditran and on some other compounds. This finding was followed up with us by the US Army.

        When I was in the US, we applied to the FDA for an investigator’s IND to further study these effects. A psychiatrist in the US contacted us for permission to access our FDA submission; we agreed and he went on to obtain a patent for the use of Tacrine to treat tricyclic antidepressant overdose. He reported that it was effective for this purpose. 

        Some years later, there were some reports in the US on its use in the treatment of Alzheimer’s dementia. Then some reports appeared in the US literature of its efficacy for the benefit of established cases of such dementia. Tacrine was then patented by some of these investigators for treatment to improve and benefit patients with this condition. It was marketed for this purpose and approved for this indication. Subsequently, this therapeutic finding was published widely in the literature and also presented at psychiatric meetings and Alzheimer meetings -- a really important breakthrough for this condition. After several years of further clinical use, it was decided that maybe this level of therapeutic activity was not upheld. 

        However, the next step in the story was a little surprising. Apparently, some investigators proposed that Tacrine was beneficial rather as a compound that could significantly reduce the rate of decline of Alzheimer’s dementia to a degree that was statistically and therapeutically significant. This data was then submitted to the FDA and it was approved for this indication and remarketed. It was on the market for a couple of years and then disappeared.

        Here, we have an important story in the history of psychopharmacology. How is it that the drug could have progressed through each one of these many steps? There are always many internal reviews within the pharmaceutical industry involving experts in the field as consultants. Then many papers are published in the scientific journals and the work discussed at many scientific meetings.  Also, Tacrine was reapproved each time for a different indication by the FDA.

        I think that this tale requires some careful thought by some members of INHN and the psychopharmacological community at large.

        I think there is something wrong, doc.

March 12, 2020