The influence of stress, in conjunction with infection, also was introduced early on as a possible cause . The pace of ‘modern’ society was blamed  and still is . The patients themselves often believe that a virus together with stress were the causative agents .
The involvement of stress in the pathogenesis of this illness seems clear for most physicians, and many patients acknowledge the influence of this factor on the natural course of symptoms. Stress can be divided into long-term and short-term subgroups which have different effects on human physiology. There is also the influence of biological adaptation. At low levels, stress may actually improve some aspects of immune function . However, most types of stress have been shown to impair immune system function and, in general, the immune defence against viral illness . One example is herpes simplex which rests, latent, in the neurones, but is susceptible to reactivation by a variety of factors including immune suppression, fever, hormonal changes, and physical and emotional stress.
Perhaps the best studied activation system in the body is the hypothalamus–pituitary–adrenocortical (HPA) axis. This system is an example of a negative feedback circuit. Corticotropin-releasing hormone (CRH) released from the hypothalamus stimulates the pituitary gland to secrete adrenocorticotropin hormone (ACTH), which in turn stimulates the adrenal cortex to secrete cortisol into the blood. An increase in the concentration of cortisol in the blood results in a direct inhibition of CRH secretion by the hypothalamus.
Under chronic stress, different disturbances in this feedback can occur. In conditions of deep depression, the whole HPA axis seems to be hyperactive, where cortisol does not inhibit the secretion of CRH in the normal way [131, 132]. In post-traumatic stress disorder the basal secretion of cortisol is low, but when the individual is reminded of the horrible events he/she experienced, the axis is immediately awakened . In CFS it seems, instead, that the CRH activity has become attenuated. As CRH is the impetus, the activity of the whole axis is generally low . So far no one has been able to determine the mechanisms behind these three types of disturbances, but research in animals and humans has confirmed these abnormal patterns of function [30, 103, 134–141].
A dysregulation of the HPA axis was found in patients with fibromyalgia, a condition sharing some characteristics with CFS. These patients also have increased levels of the neuropeptide substance P in cerebrospinal fluid which, however, was detected within normal range in CFS patients , thus making it a potential biological differential marker.
As an example of the effects of a single stress factor, the effects of Hurricane Andrew were studied in CFS patients in Florida . It was found that patients from the high impact area had significant increases in physician-related clinical relapses and an exacerbation in frequency of several categories of self-reported physical symptoms compared to patients from lower impact areas. Illness burden also was significantly increased. The patients’ post-hurricane distress response was the single strongest predictor of the probability and severity of relapse and functional impairment. Optimism and social support were significantly associated with lower illness burden after the hurricane.
We know that there is a common chemical language, only partly deciphered, for the brain, immune, and endocrine systems . The immune and neuroendocrine systems represent a totally integrated information circuit, a result of sharing ligands and their receptors. The immune system communicates with the neuroendocrine system and can, at a local level, itself act as an effective endocrine organ. It is probable that small perturbations in immunological stimuli may cause major fluctuations in endocrine status .
Studies of different treatment schemes are not easy to perform in this condition. This is probably a consequence of the heterogeneity of patient populations and complexity of origin. Therefore, data have to be analysed comparing different groups of patients (e.g. those with gradual versus sudden onset, symptom severity, etc.) and control groups are needed. The use of a common case definition in defining subjects of all treatment studies should help this problem, but not eliminate it: most investigators believe that the cases circumscribed by the current CDC case definition are probably still a heterogeneous group. The hope is that application of the case definition will reduce heterogeneity, although it probably will not eliminate it. As the definition of CFS becomes more accepted and used by international research groups, comparable studies should become easier to perform. The natural course of CFS is still largely unknown and the cyclic nature of the symptoms presents problems when treatments are being evaluated. Also, the absence of objective markers of this illness makes evaluation more difficult and dependent on subjective measurements. Thus, studies are not easy to design and evaluate.
Relatively few large randomized trials of therapy have been conducted. Many clinicians report, from uncontrolled experience, that low doses of tricyclic agents seem to help patients – particularly in alleviating the sleep problems. This is of interest because of the proven value of low-dose tricyclics in a very similar syndrome, fibromyalgia [148, 149]. Patients usually have difficulty tolerating doses used for treatment of depression, as sedative and anticholinergic effects cause disturbing side-effects. Therefore, other classes of antidepressant drugs have been tried. Selective serotonin reuptake antagonists (SSRA) should, theoretically, be beneficial, as serotonergic pathways also play a role in sleep disturbances and sympathetic drive. A double-blinded study using fluoxetine (Prozac), however, showed no effect . One small study of a monoamine oxidase inhibitor (phenelzine) showed some improvement of symptoms . In practice, many patients are reluctant to take these drugs.
The antiviral medication, acyclovir, was found ineffective ; however, this medication has minimal or no in vitro activity against the viruses that have most frequently been associated with CFS. In a large randomized trial, the immune modulating drug, Ampligen, was found to have an effect on both symptoms and objective parameters over a 26-week period, but there was no evaluation of the durability of the improvement following the end of therapy . Amantadine  has also been tried, not because of its antiviral properties, but because of its central effects in releasing noradrenaline and dopamine, retarding reuptake of these transmitters, and its demonstrated value in improving the fatigue seen in some patients with multiple sclerosis. None have proven efficient in relieving CFS symptoms.
Other drugs studied include the oral antihistamine terfenadine  and alpha-interferon . Neither showed any therapeutic effect in CFS patients. Carnitine, essential for mitochondrial energy production, has been found to be beneficial to the patients in one study . Immunologic therapy with high dosages of gammaglobulin given intravenously have not been found to be effective [157, 158]. Low-dose hydrocortisone was associated with some improvement in symptoms but the degree of adrenal suppression precludes its practical use for CFS .
Cognitive behavioural therapy has been used in different schemes – either in groups [160, 161] or, more successfully, on an individual basis . The latter form proved effective in moderating symptoms, at one-year follow-up. Cognitive behaviour therapy emphasizes self-help. The goal is to help the patient to change unhelpful cognitions and behaviour. Although the effect has rarely so far been shown to be curative, the effect is substantial. At present, intensive individual CBT administered by trained staff is one treatment of choice .
Clinical management of conditions such as CFS is not developed at all levels of the health care system. This causes problems for many clinicians coming into contact with this illness for the first time, as information regarding diagnosis and treatment is not readily available . Updated information on CFS and distribution of such to clinicians is important and needed.
Trust must be established between the patient and doctor, as a thorough clinical investigation, to exclude other probable illness causes, is of utmost importance. A complete detailed life history must include both physical and psychological problems, which often require the expertise of a specialist to exclude them.
If the diagnosis of CFS is established, information on current knowledge should be given to the patient and repeated. This includes possible triggering events (e.g. infections in a predisposed individual), and factors that can perpetuate the condition. Cognitive behavioural therapy should be used on an individual basis if possible. A consistent pattern of living – including work, rest, sleep, and physical activity – should be applied, and a slow increase of daily activities introduced. It should be explained that even a slow increase in physical exercise can cause an exacerbation of symptoms, but often these subside with time and there is improvement.