David Janowsky:Cholinergic muscarinic mechanisms in depression and mania 

David Janowsky’s reply to Barry Blackwell’s comments


        I appreciated Barry Blackwell’s comments concerning his work studying the anticholinergic effects of tricyclic antidepressants.  Especially interesting to me was to read how his work  was conducted with fellow faculty  and/or residents and little or no outside support.  In this day and age of high technology, so much of the prestige of doing research is based on the amount of funding an investigator can capture, and the carrying out of work that has already been shown to “have promise ” by having been done before.    It is reassuring to remember that much can be accomplished with relatively simple methods and creative thinking. 

        Barry Blackwell’s work implies an important part of the adrenergic/cholinergic hypothesis    which was not covered in my  essay.  Although the anticholinergic-antimuscarinic activity of various tricyclic antidepressants differ, this  difference is not particularly related  to their efficacy, although there is some evidence that more anticholinergic tricyclic antidepressants may be more effective than less so ones.   Also, the  timing of therapeutic effects of tricyclics on depression is not related to the timing of  alleviation of enuresis,  which is probably due to an anticholinergic effect.  Such  observations have been utilized as information not particularly supportive of an adrenergic / cholinergic balance hypothesis of depression.  Counter arguments can easily be proposed. For example, tricyclic antidepressants also exert noradrenergic effects which could effect enuresis or  the anticholinergic effects are exerting  downstream effects unrelated to their potency or  it takes time to exert antidepressant effects on whatever receptors or messengers or genes,  whereas immediate receptor blocking effects occur on the bladder, etc.

        Nevertheless, the fact  remains that the data presented by Dr.  Blackwell can   be considered, as it has been, a relevant negative in the adrenergic /cholinergic balance hypothesis  of mania and depression or, conversely,  a relevant positive, since indeed imipramine for example exerts anticholinergic/antimuscarinic effects as well as it’s other effects.


January 9, 2020