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