David Janowsky:Cholinergic muscarinic mechanisms in depression and mania 

David Janowsky’s reply to Hector Warnes’ comments


        Looking at  Dr. Hector Warnes’ comments and his  extremely sophisticated and extensive  listing of most  of the known multiple pathways proposed as  relevant to the etiology of depression, I am impressed even more than ever by the complexity of these multiple pathways and their  interactions.        

        One can easily  despair of ever having an  etiological answer to the biochemical causes of depression.  Blocking or augmenting a specific  cascade may lead to a decrease in symptoms, as  in the case of centrally acting anticholinergic agents blocking muscarinic receptors and alleviating depression in humans and in animal models,  or the blocking of dopamine in mania with anti-dopaminergic agents.  However, that is probably  the easy part  compared to determining if  there are  specific trails which end up at the same place eventually,  or determining which pathways are relevant to a given malady and which are not.  Maybe following each of these trails as they become defined, using agents that block or augment  their completion at different places and their interactions,  using  animal models of depression and seeing ultimately where they converge may be a reasonable, although  exhausting  strategy of psychobiologic research.

        Dr. Warnes briefly reviews many of the main findings that my article covers. I do want to mention that I  cited the DFP work of Rowntree et al. (1950),  but our group did not actually do that work which preceded our studies  by two decades.  I also wish to mention the well-deserved credit Hector Warnes gives to the work of W.R. Hess and Ernst Gellhorn defining the precursors of the parasympathetic and sympathetic nervous system, the trophotropic and ergo tropic nervous systems 

        Dr. Warnes mentions that “it is also unlikely that scopolamine, a pan-muscarinic acetylcholine blocking agent ‘was effective in alleviating bipolar and unipolar depressive symptoms’ even if it was replicated once.”  I would say to  the above comment the following:  Who knows?  Although there have been many false starts  and ultimately discredited theories in the world of psychopharmacology, most of the major   psychiatric discoveries  ( i.e.,  antidepressants, antipsychotics, antianxiety agents) started as  uncontrolled observations of behavioral  changes, generally on a few cases.  Part of my  argument  in support of the likelihood that  scopolamine is an antidepressant is that there is much preclinical evidence supporting that possibility.    To date very few investigators have studied scopolamine's potential antidepressant effects in people, so let’s see if  it works or not before deciding that it doesn’t.  

        Similarly, Dr. Warnes  comments regarding  our review of acetylcholine’s role in regulating stress,  saying: “In my own view it is unlikely that the effect of stress would induce ‘anxiety and dysphoria’ as well as would invariable increase blood pressure and pulse rate, release of cortisol, ACTH, epinephrine and beta-endorphin based on a cholinergic surge.  Again, there is much preclinical evidence that acetylcholine release regulates stress hormones  and stress hormones activate acetylcholine”  (Dulawa and Janowsky 2019;  Janowsky and Risch 1984). Especially relevant in support of an acetylcholine-stress relationship  is the fact that the major  manifestations of stress, i.e.,  endocrine, cardiovascular, anxiety and depression/dysphoria are mimicked by physostigmine, effects blocked by scopolamine, but not by methscopolamine, which does not enter the brain.  Significantly, when the peripheral effects of  acetylcholine are blocked at the end organ level,  the central effects of physostigmine can dramatically increase blood pressure and pulse rate, whereas scopolamine lowers it.



Dulawa SC, Janowsky DS. Cholinergic regulation of mood: from basic and clinical studies to emerging therapeutics. Mol. Psychiatry 2019; 24: 694-709.

Janowsky DS, Risch SC. Cholinomimetic and anticholinergic drugs used to investigate an acetylcholine hypothesis of affective disorder and stress. Drug Dev Res. 1984; 4:125-42.

Rowntree DW, Nevin S, Wilson A. The effects of diisopropylfluorophosphonate in schizophrenia and manic depressive psychosis. J Neurol. Neurosurg, Psychiat. 1950; 13:47-62


December 19, 2019