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• Various observations on this study
  Tom P Kindlon
  Published on: 13 April 2016

• Published on: 13 April 2016

  Various observations on this study

  • Tom P Kindlon, Information Officer (voluntary position)

  Dear Editor,

  The authors report that "those taking antidepressants had a higher median (interquartile range) body mass ratio (25.0 (21.4-27.6) versus 22.0 (20.0-25.2) (p=0.03) and a shorter median (interquartile range) time on the treadmill (8.6 (6-11) versus 11.0 (8-12) minutes) (p=0.02). They also had a significantly lower mean (SD) peak VO2 (27.9 (9.0) versus 32.8 (7.0) ml/kg/min) (p=0.02)." In the discussion...

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  Dear Editor,

  The authors report that "those taking antidepressants had a higher median (interquartile range) body mass ratio (25.0 (21.4-27.6) versus 22.0 (20.0-25.2) (p=0.03) and a shorter median (interquartile range) time on the treadmill (8.6 (6-11) versus 11.0 (8-12) minutes) (p=0.02). They also had a significantly lower mean (SD) peak VO2 (27.9 (9.0) versus 32.8 (7.0) ml/kg/min) (p=0.02)." In the discussion section, the authors then say, "body mass index has been previously noted in subjects reporting fatigue. This particular association, when combined with both the known and this study's association between antidepressants and body mass index, suggests that weight reduction might be a useful treatment strategy in some patients with CFS."

  Given in particular, the mention of weight reduction, I find it strange that at this stage the authors don't comment that their results might influence prescribing patterns with regards to some CFS patients i.e. the corollary of the sentence above would be that avoiding antidepressants "might be a useful treatment strategy in some patients with CFS". So I'm doing it now.

  In my experience, antidepressants are being prescribed for all sorts of symptoms in CFS patients: pain, sleep, IBS-type symptoms, mental fatigue/cognitive problems, low blood pressure/orthostatic issues, depression to name a few. Following the reasoning above, it would suggest that other methods may be preferable.

  Since this study was published, a study by Welsh researchers[1] had some intereresting things to say on the use of antidepressants in CFS patients.

  In a study of 23 patients and 42 healthy controls, they found that: "The serum [free Trp]/[CAA] ratio was 43% higher in CFS patients, due to a 48% higher [free Trp]. [Total Trp] was also significantly higher (by 19%) in CFS patients, and, although the [total Trp]/[CAA] ratio did not differ significantly between the control and patient groups, the difference became significant when the results were co-varied with age and gender. [CAA] was not significantly different between groups, but was significantly lower in females, compared to males, of the CFS patient group." The authors go on to say: "We have provisionally identified two subgroups of CFS patients, one with normal serotonin and the other with a high serotonin status."

  The discussion section of the paper explains the relevance of some of the findings. It also re-iterates my point that antidepressants are often used to try to treat various symptoms associated with CFS: "If the present results are confirmed, our proposals should have important implications for the pharmacotherapy of the CFS. Serotonin-modifying and other antidepressants are prescribed to CFS patients to treat depression (if present), pain and/or fatigue. However, CFS patients with serotonin excess should not be exposed to, and are unlikely to benefit from, serotonin-modifying antidepressants, particularly selective serotonin-re- uptake inhibitors (SSRIs), to avoid a potential excessive serotonin hyperactivity. Similarly, in view of the well known Trp-SSRI interaction, the latter should not be prescribed to CFS patients with high Trp levels or increased availability to the brain. By contrast, as suggested by a meta-analysis of previous pharmacological trials (O'Malley et al., 1999) and a survey of psychiatrists (Hickie et al., 1999), tricyclic antidepressants have a greater likelihood of efficacy than SSRIs, are preferred by patients with chronic pain, and have superior antinociceptive properties in fibromyalgia (McQuay et al., 1996). Also, our clinical impression suggests that tricyclic antidepressants improve sleep disturbances in, and are better tolerated than SSRIs by, CFS patients."

  An alternative explanation could be read into the association between exercise tolerance and body mass index: the more severely affected patients are with CFS, because of some (as yet unknown) disease process associated with some or all cases of CFS, the less able they are to exercise and so the harder it is for them to keep their weight to optimum levels. (Or alternatively the disease process increases their weight by some other means.)

  Similarly muscle weakness (which also featured in regression models of exercise tolerance) could be a marker of the severity of the disease process in some or all cases of CFS - I say "some or all cases" because, as Lane points out in the accompanying editorial[2], "it is increasingly recognised that chronic fatigue syndrome (CFS) is heterogeneous... Failure to recognise this heterogeneity prejudices attempts to understand CFS in cross sectional studies." He pointed out that some research that had been published at that time suggested "some patients with CFS have a form of metabolic myopathy". He subsequently published a paper[3] which found that "there is an association between abnormal lactate response to exercise, reflecting impaired muscle energy metabolism, and the presence of enterovirus sequences in muscle in a proportion of CFS patients." This was found by combining a subanaerobic threshold exercise test (SATET) and a RT-NPCR test for viruses: "Muscle biopsy samples from 20.8% of the CFS patients were positive for enterovirus sequences by RT-NPCR, while all the 29 control samples were negative; 58.3% of the CFS patients had a SATET+ response. Nine of the 10 enterovirus positive cases were among the 28 SATET+ patients (32.1%), compared with only one (5%) of the 20 SATET- patients. PCR products were most closely related to coxsackie B virus."

  An empirically derived definition for "ME/CFS"[4] has included "generalized muscle weakness". "Muscle Weakness" has also been used in other definitions of ME[5]. (CFS and ME are terms that are sometimes used interchangeably).

  It would have been interesting if information on the results of those who had done graded exercise therapy had been included in this study, both at the end of the 12 week intervention and at follow-up. There are a lot of references to the trial but the paper itself[6] only gives bits and pieces of the data of measures included in the current study.

  It is interesting to note that the trial[6] did not prove graded exercise therapy was a panacea for CFS, which has been demonstrated numerically in a recent meta-analysis[7], which analysed the data (the authors of the meta-analysis reported that they contacted authors of the studies for missing data so they may have had access to data we are not given).

  For the studies under review, the Cohen's d value (an effect measure) was calculated using the following method: "Separate mean effect sizes were calculated for each category of outcome variable (e.g., fatigue self- rating) and for each type of outcome variable (mental, physical, and mixed mental and physical). Studies generally included multiple outcome measures. For all analyses except those that compared different categories or types of outcome variables, we used the mean effect size of all the relevant outcome variables of the study."

  Malouff et al[7] calculated the d value for the study[6] as 0.46 (95% CI: 0.03-0.95). For anyone unfamiliar with Cohen's d values, they are not bounded by 1; also, the higher the score, the bigger the "effect size" i.e. the more "effective" a treatment was found to be. Cohen's d values are considered to be a small effect size at 0.2, a moderate effect size at 0.5, and a large effect size at 0.8[7].

  That Graded Exercise Therapy is not a panacea for CFS is not surprising given the aforementioned association Lane found[3] between enteroviruses and abnormalities on exercise testing in some CFS patients.

  REFERENCES

  [1] Badawy AA, Morgan CJ, Llewelyn MB, Albuquerque SR, Farmer A.
  Heterogeneity of serum tryptophan concentration and availability to the brain in patients with the chronic fatigue syndrome. J Psychopharmacol.
  2005 Dec;19(4):385-91.

  [2] Lane R.
  Chronic fatigue syndrome: is it physical?
  J Neurol Neurosurg Psychiatry. 2000 Sep;69(3):289.

  [3] Lane RJ, Soteriou BA, Zhang H, Archard LC
  Enterovirus related metabolic myopathy: a postviral fatigue syndrome.
  J Neurol Neurosurg Psychiatry. 2003 Oct;74(10):1382-6.

  [4] Osoba T, Pheby D, Gray S, Nacul L.
  The Development of an Epidemiological Definition for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome.
  Journal of Chronic Fatigue Syndrome, Vol. 14(4), 2007

  [5] Goudsmit EM, Stouten B, Howes S.
  Fatigue in Myalgic Encephalomyelitis.
  Bulletin of the IACFS/ME - Volume 16, Issue 3. http://www.iacfsme.org/BULLETINFALL2008/Fall08GoudsmitFatigueinMyalgicEnceph/tabid/292/Default.aspx

  [6] Fulcher KY, White PD
  Randomised controlled trial of graded exercise in patients with the chronic fatigue syndrome.
  BMJ 1997, 314:1647 -1652.

  [7] Malouff, J. M., et al.
  Efficacy of cognitive behavioral therapy for chronic fatigue syndrome: A meta-analysis.
  Clinical Psychology Review (2007), doi:10.1016/j.cpr.2007.10.004

  [8] Cohen J
  Statistical power analysis for the behavioural sciences.
  Edited by: 2. New Jersey: Lawrence Erlbaum; 1988.

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  Conflict of Interest:
  None declared.

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