David Janowsky:Cholinergic muscarinic mechanisms in depression and mania 

Hector Warnes’ comments


          Based on Thomas Ban's report (1974) of the role of central cholinergic mechanisms in depression Janowsky, 45 years later, updated his own views on the role of the trophotropic system in mania and depression. Janowsky in his review cited Willougby (1889), who in a Lancet publication observed that pilocarpine (a cholinergic agonist) antagonized mania and 60 years later Janowsky observed that an acetylcholinesterase inhibitor (DFP) had antimanic and mood depressive effects in manics and depressant effects on depressive subjects. Tom Ban (1974) citing Selbach supported the view of the trophotropic or parasympathetic predominance over the ergotrophic nervous system in depression.

          The anticholinergic effects of imipramine leading to the shift of mood in the depressed patient appear to support this view. Janowsky et al (1972) demonstrated that the infusion of a short-acting and reversible acetyl-cholinesterase inhibitor (physostigmine) "rapidly caused depression and anergia in patients with major depression and dramatically reversed manic symptoms in manic patients." This effect was reversed by the dopamine/norepinephrine releasing methylphenidate (Ritalin) which antagonized physostigmine-induced lethargy and depression. It was further noted that depression-prone patients may suffer from a cholinergic supersensitivity and other cholinergic agents, such acetylcholine, pilocarpine, arecholine, deanol and so on, may induce anxiety and depression in bipolar patients and antagonize mania in manic patients.

          Further support of Janowsky's hypothesis was observed in the depressive effect of ACTH and cortisol along with the short REM latency and increased density of REM sleep observed during major depressive disorders (REM sleep is triggered by a cholinergic mechanism). This REM latency and increased density may also be induced by cholinergic drugs and antagonized by the centrally acting anti-muscarinic agent scopolamine.

          Janowsky cited other studies which found choline to be increased in brains of depressed patients and finally his own study of the effect of stress by increasing central acethylcholine "probably due to central effects of corticotrophin releasing factor." In my own view, it is unlikely that the effect of stress would induce "anxiety and dysphoria" or would invariably increase blood pressure and pulse rate, release of cortisol, ACTH, epinephrine and beta-endorphine based on a cholinergic surge. 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.

          Recently, ketamine (Ketalar), a NMDA receptor antagonist, was found to be effective in antidepressant resistant patients with major depression. However, we cannot disagree with Janowsky on the possible cascade of a number of neurotransmitters, neuropeptides and neuromodulators induced by scopolamine or other agents which may activate a sequence of messengers including protein kinase A, brain-derived neurotrophic factor, monoaminergic neurotransmitters, norepinephrine, dopamine, GABA interneurons, SERT, vesicular glutamate transport I, voltage dependent calcium channels, etc. In animal models of depression it would appear that stimulation of nicotinic receptors has antidepressant and anxiolytic effects.

          Neurotransmitters are chemical messengers and their interactions are either excitatory (e.g., acetylcholine, glutamate, norepinephrine), inhibitory (GABA, glycine) or modulatory (e.g., dopamine, serotonin, histamine). Second messenger molecules include cyclic AMP, GMP, inositol triphosphate, diacylglycerol and calcium. They trigger intracellular signal transduction cascade via the phosphoinositol signaling pathway and the G-protein-coupled receptor (Reith 2000).

          Many signalling pathways have been discovered which are capable of triggering a cascade that ultimately acts on the cell nucleus. The first messenger gives rise to the appearance of a second messenger, such as cyclic AMP or cyclic GMP, which in turn triggers a third messenger (CREB), a fourth messenger and so forth. In the cited book several chapters are illuminating on the various cascades that affect brain processes in health and disease, particularly the chapter by Li, Andreapoulos and Warsch on the role of inflammatory cytokine targets for antidepressant therapy. Ronald S. Duman (2007) reported findings of lower levels of brain-derived neurotrophic factor (BDNF) in depressed patients which are reversed with antidepressant treatment; BDNF is mediated by tyrosine kinase receptor (TrkB) that when stimulated leads to activation of several intracellular pathways including RAS-microtubule-associated proteinkinase (MAPK) and phosphatidylinositol-3 kinase (PI3K)/serine threonine kinase (AKT) (Duman el al. 2007)

          It becomes obvious that the cross-talk between different signalling cascades opens many possibilities for gene expression. Changes of genomic expression induced by antidepressants are mediated by different cascades triggered by different mechanisms ending in a final common pathway. The latest view is that pharmacogenomics would lead to the discovery of specific drugs for specific patients with specific illnesses, maximizing the therapeutic effects and minimizing adverse effects. In the abstract of a most recent paper, van Erkhuisen, Janowsky, Olivier et al. (2015) reach a rather skeptical conclusion: "Despite increasing evidence supporting this hypothesis, a relationship between these two neurotransmitter systems (muscarinic and nicotinic acetylcholine receptors in depression and dopamine reuptake transporters in mania) that could explain cycling between these two states is missing. Further studies should focus on the influence of environmental stimuli and genetic susceptibility that may affect the affect the catecholaminergic-cholinergic balance underlying cycling between the affective states."

          We must keep in mind the extraordinary discoveries of W.R. Hess (1949) and the monumental work of Ernst Gellhorn (1967) on the Ergotropic and the Trophotropic autonomic nervous system, the former linked with the fight-flight responses and the latter with relaxation, digestion, sleep and so on. The trophotropic system actively dampens or inhibits the activity of the ergotropic system. This controversy reminds me of a recent one regarding the purinergic hypothesis of the bipolar disorder which proposes that in this disorder there is an increase of the turn over of adenosine which has sedative inhibiting, anticonvulsive and anti-kindling properties. Originally, an increase of uric acid during the manic phase of the bipolar disorder was found.



Gellhorn E. Principles of autonomic-somatic Integration. Minneapolis-University of Minnesota Press, 1967.

Hess WR. Das Zwischenhirn, Basel, Schwabe, 1949.

Charney DS, Buxbaum JD, Sklar P, Nestler EJ, editors. Neurobiology of Mental Illness 4th Edition Oxford University Press, New York, 2013. (REFERENCE NOT CITED)

Reith MEA, editor. Cerebral Signal transduction. From First to Fourth Messengers. Humana Press, Totowa, New Jersey, 2000.

van Erkhuisen J, Janowsky DS, Olivier B, Minassian A, Perry W, Young JW, Geyer MA. The catecholaminergic-cholinergic balance hypothesis of bipolar disorder revisited. European J. Pharmacology 2015,753;114-26.


October 10, 2019