David Janowsky:Cholinergic muscarinic mechanisms in depression and mania


Hector Warnes’ reply to Samuel Gershon’s comment on his response to David Janowsky’s reply to his (Warnes) comment


        Experimental and clinical studies have shown that unremitting chronic stressful events and chronic refractory depression (an undoubtedly heterogenous condition) are associated with loss of neurons and glial cells particularly in the hippocampus and prefrontal cortex (Duman and Voleti 2012). The cholinergic neurons in the basal forebrain (i.e., the nucleus basalis de Meynert) project widespread innervation to the cortex. Duman and Voleti in their excellent study put forward the view that anti-depressants of rapid action are associated with activation of glutamate transmission and induction of synaptogenesis which in turn liberate neurotrophic factors such as brain derived neurotrophic factor (BDNF) thus fostering neuroplasticity and neurogenesis. Alongside the action of ketamine (a non monoaminergic antidepressant) is a N-methyl-D-Aspartate (NMDA) receptor antagonist which also induces cholinergic neuromodulation via hyperpolarization of nicotinic acetyl-choline ion channels and glutamate stimulation (a different mechanism of action than the inhibitors of the reuptake of serotonin).

        In a most clarifying paper Sleigh, Harvey and Voss (2014) explored the finest pathways of the mechanism of action of ketamine which complements Duman and Voleti’s (2012) views of accelerating the antidepressant effect via the glutamate pathways. It has further been shown that chronic depression which is refractory to treatment (shown by one third of the endogenous depressives) may develop neurocognitive or other symptoms of dementia. Clinically and in animal experimentation this has been shown to be the case. Perhaps the nicotinic ionotropic receptors are stimulated via the sympathetic nervous system.

        Scopolamine (Hyoscine), a muscarinic acetylcholine receptor antagonist, has also been shown to improve patients with treatment resistant depression (Berman, Capiello, Anand et al. 2000). Scopolamine, belonging to the family of the Solanaceas (Hyosciamus niger and albus, atropa belladonna, mandragora officinarum and datura stramonium), is a psychotropic compound given by doctors for centuries. It is contradictory to treat chronic treatment-resistant depression that eventually changes in a dementing syndrome with Rivastigmine or Exelon Patch if we presume that the depression shall worsen with a cholinergic compound. Looking up the side effects of Rivastigmine I noticed that it causes depression in about 6% of cases (which is a small number) while more than 50 % of patients noticed an improvement in their neurocognitive and executive abilities. Anxiety was reported in 6% of cases under treatment. Rivastigmine is a reversible cholinesterase inhibitor. Perhaps the nicotinic ionotropic receptors are stimulated via the sympathetic nervous system.

        I would be most grateful to Professor Janowsky if he could comment on the 2012 Duman and Voleti paper. I may be mistaken if I suggest that there may be a muscarinic mechanism in the chronic depressive which might be alleviated with enhancing the nicotinic pathways.

        It is also clear that the action of ketamine and/or scopolamine would last at most seven days and should be given in the short term with an antidepressant that may be effective only after a few weeks. A potentially good biological marker would be the accumulation of tau proteins in the spinal fluid in patients with chronic treatment resistant depressive with increasing neurocognitive symptoms.

        In my last comments on ketamine I neglected to mention that it not only blockades NMDA channels but provokes a hyperpolarization of nicotinic cholinergic neuromodulation and inhibits acetyl-choline ion channels (Sleigh, Harvey and Voss 2014). The latter effect may explain the depressogenic action of muscarinic cholinergic drugs.

        A new antidepressant has also been studied: a neuropeptide galanin which through its receptors (GAL R 2 and GAL3) leads to antidepressant anticonvulsant and neurogenesis promoting effects (Murck, Held, Ziegenbien et al 2004; Lu and Sharkey 2007).




Berman RM, Cappiello A, Anand A, Oren DA, Heninger GR, Charney DS, Krystal JH. Antidepressant effects of ketamine in depressed patients. Biol.Psychiatry. 2000; 47:351-4. 

Duman RS, Voleti B. Signaling pathways underlying the pathophysiology and treatment of depression: novel mechanisms for rapid-acting agents. Trends Neurosci. 2012; 35(1):47-56.  

Lu X, Sharkey L. The Brain Galanin Receptors: Target for Novel Antidepressant drugs. Neurol. Dis. Drug Targets. 2007; 6(3):183-92. 

Murck H, Held K, Ziegenbein M,  Künzel H, Holsboer F, Steiger A. Intravenous administration of the neuropeptide galanin has fast antidepressant efficacy and affects the sleep EEG. Psychoneuroendocrinology. 2004; 29(9): 1205-11. 

Sleigh J, Harvey M, Voss L, Denny B. Ketamine: more mechanism of action than just NMDA blockade. Trends in Anaesthesia and Critical Care. 2014; 4(2-3):76-81.


November 26, 2020