Comment
Ever since neurologist George Miller Beard coined the term neurasthenia in the 19th century,1 dozens of names have been used to describe illnesses resembling chronic fatigue syndrome. The diverse nomenclature reflects heterogeneity in the disorder’s conceptualisation, spawning terms as divergent as chronic Epstein–Barr virus, epidemic neuromyasthenia, systemic exertion intolerance disease, post-viral fatigue syndrome, myalgic encephalomyelitis, and chronic fatigue immune dysfunction syndrome. The diversity in nomenclature parallels the diversity in therapies assessed for this frequently refractory cluster of symptoms, which include pharmacological (eg, fluoxetine, rintatolimod, galantamine), psychological (eg, cognitive therapy, adaptive pacing therapy), and lifestyle interventions (eg, exercise).2 In Lancet Psychiatry, Michael Sharpe and colleagues3 report the 2·5 year long-term follow-up of the PACE trial, a 2011 multicentre, four-arm, randomised controlled trial of 641 individuals with diagnosed chronic fatigue syndrome to compare the effect of four nonphamacological therapies (standard medical care alone [SMC]), adaptive pacing therapy [APT], graded exercise therapy [GET], and cognitive behavioural therapy [CBT]) on self-rated levels of fatigue and physical functioning.4 Initial results of the trial showed clear superiority of augmenting SMC with CBT or GET, but not APT, to SMC alone on fatigue and physical function at 12 months.4 For their follow-up study, Sharpe and colleagues3 accumulated postal responses from 481 of the original 641 participants, who reported their level of fatigue, physical functioning, and whether they had received any further study treatments since study conclusion. Interestingly, individuals who originally received CBT and GET maintained improvement in fatigue and physical functioning at follow-up (median 31 months after randomisation; range 24–53), irrespective of whether they received any further treatment. Individuals who received APT or SMC alone displayed improvement in fatigue and physical functioning irrespective of receiving further treatment, such that no difference in outcomes was evident between any of the original treatment groups at long-term follow-up. Finally, individuals allocated to APT or SMC alone in the original trial were more likely than other participants to
receive CBT, GET, or both treatments, during the followup period.3 The authors hypothesise that the improvement in the APT and SMC only groups might be attributed to the effects of post-trial CBT or GET, because more people from these groups accessed these therapies during follow-up. However, improvement was observed in these groups irrespective of whether these treatments were received, and thus this hypothesis remains unproven. Overall, our interpretation of these results is that structured CBT and GET seems to accelerate improvement of self-rated symptoms of chronic fatigue syndrome compared with SMC or SMC augmented with APT, an important finding in an illness with few treatment options and substantial morbidity. But why would these therapies accelerate symptom improvement? The boundaries of chronic fatigue syndrome and related entities are not clear and considerably overlap with other neuropsychiatric disorders (eg, depression). Theories about the pathophysiology of chronic fatigue syndrome might be best considered when divided into aetiopathogenic (casual) factors and neurobiological manifestations. Hypothesised causal factors might include infection, environmental exposures, translocation of gut commensal bacteria, allergies, and physiological and psychosocial stress.5 These factors theoretically affect neurobiological processes involved in a wide range of neuropsychiatric disorders, including neuroendocrinology, neurotransmission, neuroplasticity, oxidative and nitrosative stress regulation, mitochondrial function, and neuroimmunology.6 The neuroimmunology of fatigue is increasingly researched, showing associations with increased concentrations of proinflammatory cytokines, oxidative stress, and activated Toll-like receptors.6 Single nucleotide polymorphisms for genes representing the complement cascade, chemokines, and Toll-like receptor signalling have been associated with altered immune responses seen in chronic fatigue syndrome.5 Additionally, a 2014 neuroimaging study in patients with chronic fatigue syndrome used positron emission tomography to show evidence of widespread glial activation (representing neuroinflammation) with degree of activation associated with severity of neuropsychological symptoms (eg, cognitive impairment, pain, and depression).7 These neuroimmunological
www.thelancet.com/psychiatry Published online October 28, 2015 http://dx.doi.org/10.1016/S2215-0366(15)00475-7
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Chronic fatigue syndrome: what is it and how to treat?
Lancet Psychiatry 2015 Published Online October 28, 2015 http://dx.doi.org/10.1016/ S2215-0366(15)00475-7 See Online/Articles http://dx.doi.org/10.1016/ S2215-0366(15)00317-X
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Comment
findings could assist understanding for effectiveness of the PACE trial treatments, as well as other novel interventions for chronic fatigue syndrome. For example, exercise therapy might improve symptoms of chronic fatigue syndrome thorough beneficial effects on neuronal functions via anti-inflammatory and antioxidant actions.8 Intriguingly, CBT has also been suggested to have antiinflammatory properties.9 An increased understanding of the pathogenesis of chronic fatigue syndrome could lead to development of new diagnostic and therapeutic interventions. An early example of this is rituximab, a B-cell-depleting monoclonal antibody against the B-cell protein CD20, which has shown promise in early trials10 for chronic fatigue syndrome and is now being examined in a randomised controlled trial (ClinicalTrials.gov identifier: NCT02229942). New treatments like this have been sparse for many neuropsychiatric disorders over the past few decades. An increasing appreciation of the pathophysiological role of neuroimmunological pathways in these disorders opens many new avenues to explore. Recent evidence that suggests the effectiveness of mechanistically inspired therapies such as antioxidants and anti-inflammatory agents in diverse neuropsychiatric disorders supports the potential of this approach. Steven Moylan, Harris A Eyre, Michael Berk
MB reports grants from Deakin University, Cooperative Research Centres (CRC) for mental health, National Institutes of Health, National Health and Medical Research Council, Stanley Medical Research Institute, CRE in Clinical Research, Meat and Livestock Australia, University of British Columbia–Research & International, and National Natural Science Foundation of China, and reports personal fees from Janssen, Lundbeck, AstraZeneca, GlaxoSmithKline, Servier, and Lilly. SM and HAE declare no competing interests. 1 2
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Beard G. Neurasthenia, or nervous exhaustion. Boston Medical and Surgical Journal 1869; 80: 217–21. Smith ME, Haney E, McDonagh M, et al. Treatment of myalgic encephalomyelitis/chronic fatigue syndrome: a systematic review for a national institutes of health pathways to prevention workshop. Ann Intern Med 2015; 162: 841–50. Sharpe M, Goldsmith KA, Johnson AL, Chalder T, Walker J, White PD. Rehabilitative treatments for chronic fatigue syndrome: long-term follow-up from the PACE trial. Lancet 2015; published online Oct 28. http://dx.doi.org/10.1016/S2215-0366(15)00317-X. White PD, Goldsmith KA, Johnson AL, et al, for the PACE trial management group. Comparison of adaptive pacing therapy, cognitive behaviour therapy, graded exercise therapy, and specialist medical care for chronic fatigue syndrome (PACE): a randomised trial. Lancet 2011; 377: 823–36. Rajeevan MS, Dimulescu I, Murray J, Falkenberg VR, Unger ER. Pathway-focused genetic evaluation of immune and inflammation related genes with chronic fatigue syndrome. Hum Immunol 2015; published online June 24. DOI:10.1016/j.humimm.2015.06.014 2015. Morris G, Berk M, Walder K, Maes M. Central pathways causing fatigue in neuro-inflammatory and autoimmune illnesses. BMC Med 2015; 13: 28. Nakatomi Y, Mizuno K, Ishii A, et al. Neuroinflammation in patients with chronic fatigue syndrome/myalgic encephalomyelitis: An (1)(1)C-(R)-PK11195 PET Study. J Nuc Med 2014; 55: 945–50. Moylan S, Eyre HA, Maes M, Baune BT, Jacka FN, Berk M. Exercising the worry away: how inflammation, oxidative and nitrogen stress mediates the beneficial effect of physical activity on anxiety disorder symptoms and behaviours. Neurosci Biobehav Rev 2013; 37: 573–84. Irwin MR, Olmstead R, Breen EC, et al. Cognitive behavioral therapy and tai chi reverse cellular and genomic markers of inflammation in late life insomnia: a randomized controlled trial. Biol Psychiatry 2015; published online Feb 4. DOI:10.1016/j.biopsych.2015.01.010. Fluge O, Risa K, Lunde S, et al. B-lymphocyte depletion in myalgic encephalopathy/ chronic fatigue syndrome. an open-label phase II study with rituximab maintenance treatment. PloS One 2015; 10: e0129898.
School of Medicine, Deakin University, Geelong, VIC, Australia (SM, HAE, MB); Discipline of Psychiatry, University of Adelaide, Adelaide, SA, Australia (HAE); Department of Psychiatry, Orygen Research Centre, and the Florey Institute for Neuroscience Mental Health, The University of Melbourne, Parkville, VIC, Australia (MB); and Barwon Health, Geelong, VIC 3220, Australia (SM, HAE, MB)
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www.thelancet.com/psychiatry Published online October 28, 2015 http://dx.doi.org/10.1016/S2215-0366(15)00475-7
