Chronic Fatigue Syndrome and the Cholinergic Hypothesis JAMA. 2004;292:2723, Dec. 8, 2004. To the Editor: While the study by Dr Blacker and colleagues1 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 Seidman2 and Brenner et al3 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.4 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.3 Until a trial of CFS treatment with this agent is undertaken, I believe the cholinergic hypothesis deserves investigation as a plausible contributing explanation. Peter V. Madill, MD pmadill@cds1.net Sebastopol, Calif 1. Blacker CV, Greenwood DT, Wesnes KA, et al. Effect of galantamine hydrobromide in chronic fatigue syndrome: a randomized controlled trial. JAMA. 2004;292:1195-1204. 2. Soreq H, Seidman S. Acetylcholinesterase-new roles for an old actor. Nat Rev Neurosci. 2001;2:294-302. [published correction appears in Nat Rev Neurosci. 2001;2:670]. 3. Brenner T, Hamra-Amitay Y, Evron T, Boneva N, Seidman S, Soreq H. The role of readthrough acetylcholinesterase in the pathophysiology of myasthenia gravis. FASEB J. 2003;17:214-222. 4. Hasselmo ME, Linster C. Acetylcholine and frontal cortex "signal-to-noise ratio." In: Miller BL, Cunningham JL. The Frontal Lobes. New York, NY: Guilford Press; 1999:139-158. Letters Section Editor: Robert M. Golub, MD, Senior Editor. _________________________ Chronic Fatigue Syndrome and the Cholinergic Hypothesis-Reply JAMA. 2004;292:2723, Dec. 8, 2004. In Reply: My colleagues and I were not proposing that our study was an exhaustive test of cholinergic mechanisms. However, anticholinesterases are now being used increasingly widely to treat other neurocognitive disorders such as traumatic brain injury and Parkinson disease. This, coupled with other observations in CFS, such as marked sensitivity to the anticholinergic adverse effects of tricyclic antidepressants, findings of cognitive impairment, and previous positive (and negative) trials involving both bethanechol and galantamine, led to a hypothesis that our many coinvestigators found persuasive. Our finding that these patients had measurable cognitive impairment that did not show a response to an anticholinesterase is an invitation for further research; we await a trial such as that recommended by Dr Madill. C. V. Russell Blacker, MD, FRCPsych c.v.r.blacker@btinternet.com Department of Health and Social Sciences Wonford House Hospital Exeter, England Letters Section Editor: Robert M. Golub, MD, Senior Editor. _________________________ Note: This exchange is over the article "Effect of Galantamine Hydrobromide in Chronic Fatigue Syndrome - A Randomized Controlled Trial," JAMA. 2004;292:1195-1204, the abstract of which can be read at http://listserv.nodak.edu/scripts/wa.exe?A2=ind0409A&L=co-cure&P=R8550 .