RETURN TO TABLE OF CONTENTS
Winter 2004 

Research News
The latest information on research, treatment and diagnosis of CFIDS and related disorders

Serotonin gene abnormality in CFS
Japanese scientists have found an aberration in some CFS patients’ serotonin gene and hypothesize that it may be related to the pathophysiology of the condition. Serotonin is a brain chemical that regulates sleep, appetite, pain, mood, emotion and inflammation. 

CFS patients were more likely to have rare forms of the serotonin transporter gene compared to controls. The so-called longer gene variants were seen in 40 of 156 genes from CFS patients, and only 12 of 100 genes from controls. This genetic alteration may result in a person having lower levels of active serotonin and may also increase susceptibility to CFS, according to the researchers. Serotonin interfaces with the hypothalamic-pituitary-adrenal (HPA) axis and may play a role in the endocrine abnormalities that have been found in CFS. The study was published in Biochemical and Biophysical Research Communication in November.

Serotonin inhibitor may alleviate CFS
Four out of five patients treated with granisetron, a serotonin agonist, saw marked improvements in fatigue and treated with granisetron, a serotonin agonist, saw marked improvements in fatigue and function within two weeks of starting therapy, according to an article in the September 2003 issue of Netherlands Journal of Medicine. The positive results faded two weeks after discontinuing treatment.

The promising results have led to the initiation of a placebo-controlled, blinded study. Although the present study was open-label and a placebo effect can’t be ruled out, there is a strong rationale behind the study. Increasing evidence points to an upregulation of serotonin in the pathogenesis of CFS, which would explain why serotonin agonists might be effective, and why antidepressants in the selective serotonin reuptake inhibitor (SSRI) category, such as Prozac, have not worked as well.

Editor’s note: Contradictory research findings, such as appear in the above two studies, may reflect variable study methodologies, such as different patient selection criteria or ways of interpreting findings. The only way to clear up these and other mysteries of CFIDS is through research studies which involve large numbers of patients and use proven study methodologies and techniques.

Milnacipran treats FM pain
Results of a Phase II study showed that milnacipran is effec tive in treating fibromyalgia pain and that its impact on pain is distinct from its antidepressant properties. The drug worked equally well in depressed and nondepressed FM patients, but the placebo response was stronger in depressed patients. This "suggests that the pain experienced by these patients is not directly related to their mood," according to Jay D. Kranzler, MD, PhD, of Cypress Bioscience, the sponsor of the study.

Milnacipran is a new class of drug that acts on two key neurotransmitters, norepinephrine and serotonin. It is available in 22 countries, but not yet in the U.S. Cypress Bioscience launched a Phase III clinical trial of the drug as an FM treatment in October.

CFS research, diagnosis clarified
An international group of CFS researchers offers long-needed clarification of the 1994 CFS case definition in the December 31 issue of BMC Health Services Research. The authors make a particular effort to explain "exclusionary conditions," which is a key part of the 1994 case definition, but has been difficult to interpret and apply.

Exclusionary conditions are medical or psychiatric conditions that could plausibly cause CFS symptoms, such as multiple sclerosis or chemo-therapy treatment. Because the biology of CFS is not understood, researchers must screen potential subjects for exclusionary conditions to rule out the possibility that their findings could be attributed to another condition (or set of conditions) present in the subjects.

Although the 1994

definition was written only

for research settings, it was adopted by physicians to

diagnose their patients because no alternative clinical guidelines existed. The new paper’s authors acknowledge that the concept of exclusionary conditions may have less importance in clinical practice. They state, "In the clinical setting, patients with exclusionary conditions may be diagnosed and manage as having CFS on the basis of the physician’s medical opinion as to whether the exclusionary condition is likely to be a major contributor to the patient’s fatigue." While this change seems to broaden the definition of CFS, it likely reflects how the illness is actually diagnosed by doctors.

The paper clarifies other ambiguities in the original case definition. For example, the case definition concept that "rest should not substantially alleviate fatigue" has sometimes been misinterpreted to suggest that if you feel better after resting, you do not have CFS. The authors explain that this statement was intended to distinguish CFS from the "fatigue associated with overwork that resolves when the excessive demands end."

The article also makes a concerted effort to standardize research instruments by recommending specific instruments to measure particular symptoms. One major problem in CFS research has been the use of vastly differ-ent tests to assess the same symptom (such as cognitive impairment), making it nearly impossible to compare one study’s results to another’s. If adopted by researchers, these recommendations should greatly improve comparability of research.

The full text of this article is available at www.biomedcentral.com 1472-6963/3/25.

Progesterone elevated in women with CFS

In a small Canadian study, women with CFS had significantly higher levels of progesterone and its metabolite isopregnanolone compared to healthy controls. These differences could not be attributed to medications or depression — further evidence, say the researchers, that CFS differs from depression.

The authors, writing in the February 2004 issue of Psychoneurendocrinology, suggest this progesterone elevation may explain the common finding that cortisol, another hormone, is low in CFS. Progesterone influences cortisol production, but cortisol can be inhibited if progesterone metabolism is diverted toward the production of the ring-A metabolites, particularly isopregnanolone, which was significantly elevated in the CFS group.

CFIDS Glossary: Terms You Need to Know

Agonist: A drug or chemical that combines with a cell receptor to produce a physiologic reaction typical of a naturally occurring substance. A serotonin agonist is able to mimic the effects of serotonin by stimulating activity at the brain’s serotonin receptors.

Endocrine: Glands (or the system of glands) that secrete hormones directly into the circulatory system. Hormones regulate many organs in the body, and because they have such widespread effects, many of the leading theories about CFS involve abnormalities in the endocrine system.

Metabolite: A substance produced by metabolism or by a metabolic process. Metabolism is the sum of the physical and chemical processes in the body and the process which makes energy available to an organism.

Pathophysiology: The functional changes associated with or resulting from disease or injury, as opposed to structural defects. The pathology of CFS would set the disease in motion, while the pathophysiology would explain the effects of the disease in the body.

Sources: Dictionary.com and Pharma-Lexicon.com