David Janowsky:Cholinergic muscarinic mechanisms in depression and mania 

David Janowsky’s reply to Edward Shorter’s comment

           I much appreciated Dr. Edward Shorter’s comments.  In many ways I agree with him.  Without going into great detail, there is a growing literature linking affective disorders genetically to schizophrenia. The arbitrary classifications of DSM 5 may be categoric and arbitrary and give a sense that we can effectively separate different disorders, but they may  not reflect realistic differences.  A most simple challenge to the “firewall”  concept is the observed  effectiveness of “antipsychotics” in treating depression or of antidepressants treating obsessive compulsive disorder,  so much in vogue today.  In addition, although I am obviously wedded to some extent to a balance hypothesis of mania and depression, I am sure that the reality of the situation involves a much more complex cascade of events. 

           With respect to Dr.  Shorter’s consideration of melancholia  as   being a deep-seated brain disease, a deep depression, I can add a few thoughts.  There are obvious differences between depressed mood and the full-blown presentation of  melancholic depression.  Whether  these differences lie on a biologic continuum  or are basically different diseases remains to be seen.  What I would say is that the “depressed”  patients to whom we gave physostigmine showed many of the characteristics of melancholic depression once the physostigmine exerted its effects.  These included intense  anergia; psychomotor retardation; guilt as as a cognitive manifestation; increased cortisol and ACTH and dexamethasone non -suppression; REM activation and REM latency shortening, as well as sadness, regretfulness and crying. These findings suggest to me that   physostigmine  caused more than just a change in affect alone, and maybe even caused the  deep-down depression  referenced by Dr. Shorter.  

January 2, 2020