David Janowsky:Cholinergic muscarinic mechanisms in depression and mania 

David Janowsky’s reply to Samuel Gershon’s comments


         I was very pleased to read Samuel Gershon’s generous  comments regarding my essay on “Cholinergic muscarinic mechanism in depression and mania.”  I vividly remember John Davis’ and my trip to Bellevue where we saw what I would call “New York Manics.”  How much fun that was.  I do remember that  the Bellevue “hypermanics”  were far more symptomatic than  those relatively tame individuals we treated with physostigmine in Nashville.  In any case, after giving physostigmine and going to lunch, we were amazed to see a rebound into even greater mania upon our return  ( Shopsin, Janowsky, Davis and Gershon 1975).   Of great  public health significance is the work Gershon and Shaw published in the Lancet in 1961 that Dr. Gershon mentions in his comments.  Their sentinel paper describing the depressing  effects of an organophosphorus insecticides which Dr. Gershon  describes in his comment was a first which has been followed by a large and growing literature on the depressing and other mental/emotional effects of cholinesterase inhibitors as these occur in agricultural settings, the most recent which I have found was published this year (Suarez-Lopex Jr., Hood, Suárez-Torres et al. 2019). 

         Finally, Sam Gershon and his colleagues describe a set of  sentinel “challenge” experiments which explore using phencyclidine (PCP) to antagonize the serotonergic antidepressant effects  of imipramine and the MAO inhibitor tranylcypromine  and Alpha-methyl -p- tyrosine to inhibit the synthesis of noradrenaline  in the above drug treated patients.  Significantly, only PCP antagonized the therapeutic effects of imipramine and tranylcypromine,  thereby more supporting a serotonergic role in modulating depression, and downplaying a role for noradrenaline, which had been a major factor in the catecholamine hypothesis of depression.   Finally, I want to acknowledge my appreciation of Dr. Gershon.  The timing of  generations between  psychobiologic researchers are generally shorter than in regular life, maybe 10 years, and Dr. Gershon represents what I would call the generation preceding me.  Dr. Gershon’s work in the above studies, and his pioneering work on lithium have been guiding lights to me in my career, and Dr. Gershon was immensely generous in inviting me to participate in several CINP meetings as a young  fledging researcher.  He is one of my heroes and a much-appreciated colleague and friend.



Shopsin B, Janowsky D, Davis J, Gershon S.  Rebound phenomena in manic patients following physostigmine: preliminary observations.  Neuropsychobiology. 1975;1(3):180-7.

Suarez-Lopex Jr., Hood N, Suárez-Torres J, Gahagan S, Gunnar MR, López-Paredes D. Associations of acetylcholinesterase activity with depression and anxiety symptoms among adolescents growing up near pesticide spray sites. Int J Hyg Environ Health. 2019;222(7):981-90.


December 12, 2019