Chronic Fatigue Syndrome and the Cholinergic Hypothesis

Abstract

To the Editor: While the study by Dr Blacker and colleagues demonstrates that galantamine is not an effective treatment for persons with chronic fatigue syndrome (CFS), I do not believe that this negative outcome represents an appropriate test of the cholinergic hypothesis in the pathogenesis of CFS. Soreq and Seidman and Brenner et al have demonstrated in animal models of posttraumatic stress disorder and in Gulf War syndrome (a possible syndromic relative of CFS) that cholinergic neurons produce sustained and excessive amounts of AChE-R, an altered soluble variant of acetylcholinesterase. There is evidence that the sustained production of AChE-R derails the cholinergic neurons from performing their normal “signal-to-noise ratio” determination role in healthy brain function. If there is a cholinergic contribution to the pathogenesis of CFS, it would likely be the dysregulated production of AChE-R. The failure of galantamine to favorably influence the outcome of this syndrome could then be predicted because, being a cholinesterase inhibitor, it is likely inducing overproduction of AChE-R. An example of the importance of AChE-R for diseases with impaired cholinergic balance is myasthenia gravis: in an animal model the restoration of normal cholinergic function via the administration of EN101, an “antisense oligonucleotide” drug which lowers AChE-R in blood and muscle, was shown to be much more efficacious than anticholinesterases such as galantamine. Until a trial of CFS treatment with this agent is undertaken, I believe the cholinergic hypothesis deserves investigation as a plausible contributing explanation.