David Janowsky:Cholinergic muscarinic mechanisms in depression and mania 

Hector Warnes’ response to David Janowsky’s reply

        I am grateful to Professor Janowsky's comments. I have always held his pioneer work in the highest regard.

        Particularly his observation dating from 1972 that the infusion of the short acting and reversible acetyl-cholinesterase inhibitor (physostigmine) rapidly caused depression and anergia in patients with major depression and was able to reverse manic symptoms in manic patients. At that time, I was fascinated with the hypothesis of a cholinergic supersensitivity and I am still.

        The adrenergic-cholinergic imbalance is at the heart of many disorders. It has been established that REM sleep short latency (less than 50 min.) and increased REM density in endogenous depression is caused by cholinergic upsurge during sleep and can be experimentally replicated by centrally acting physostigmine or arecholine.

        Professor Janowsky reminds us that imaging techniques demonstrated that the acetylcholine precursor choline is elevated in brains of depressed patients and decreases when depression is treated with antidepressants. Scopolamine (a pan-muscarinic acetylcholine blocking agent) is thought to have antidepressant action. We are also aware that the serum and plasma levels of the brain derived neurotrophic factor (BDNF) are decreased in depressed patients and this deficit is reversed with antidepressant.

        However, other neurotransmitters and neuromodulators are also involved in the antidepressant action besides BDNF, namely norepinephrine, dopamine, GABA, glutamate transport I, SERT, glycine and calcium channels voltage dependent. Second messenger molecules include cyclic AMP, cyclic GMP, phosphoinositol diacylglycerol and calcium. The anti-depressant effect of lithium is assumed to be caused by the latter mechanism. Hyosine or scopolamine (a solanacea-like atropa belladona) has been used for centuries but no anti-depressant effect was noted until imipramine was discovered.

        I wish indeed we could find the ultimate drug for antidepressant refractory patients but even ketamine has serious drawbacks.

February 13, 2020