Recently, Dr. Steven Moylan and others from Deakin University published a review of new advances in chronic fatigue syndrome in The Lancet, which briefly describes the research related to the PACE trial treatment, summarizes and analyzes the results of the research on the pathophysiological mechanisms of chronic fatigue syndrome in the past few years, as well as how the research results have contributed to the new treatment modalities. The following is the main content. Ever since neurologist George Miller Beard coined the term “neurasthenia” in the 19th century, a large number of terms have emerged to describe disorders similar to chronic fatigue syndrome. The diversity of nomenclature reflects the multifaceted conceptualization of the disease, e.g., chronic Epstein-Barr virus, epidemic encephalomyelitis, systemic exertion intolerance disease, post-viral fatigue syndrome, myalgic encephalomyelitis, chronic fatigue immune dysfunction syndrome. The diversity of nomenclature also reflects the diversity of treatments available for this range of symptoms, including pharmacological (e.g., fluoxetine, ampicillin, galantamine), psychiatric (e.g., cognitive therapy, adaptive pacing), and lifestyle interventions (e.g., exercise) In 2011, Michael Sharpe et al. conducted a prospective, randomized, controlled trial of chronic fatigue syndrome, and the results were published in the journal Lancet Psychiatry. Lancet Psychiatry journal. Their study compared the degree of improvement in fatigue levels and mental functioning in 641 patients with chronic fatigue syndrome after receiving non-pharmacological treatment (SMC), adaptive pacing therapy (APT), graded exercise therapy (GET), or cognitive behavioral therapy (CBT). The initial results of the trial showed that the addition of cognitive behavioral therapy or graded exercise therapy to standard medical care (SMC), with the exception of adaptive pacing therapy, resulted in significantly better outcomes than SMC alone over a 12-month period; however, subsequent follow-up showed a striking reversal. Sharpe et al. tracked the fatigue levels and mental functioning of 481 of the original participants regardless of whether they had subsequent treatment. Sharpe et al. tracked the fatigue levels and mental functioning of 481 of the original participants, with or without subsequent treatment. In the original patients who received CBT and GET, the improvements were sustained, regardless of whether or not they received subsequent treatment. Patients who received only APT or SMC showed the same characteristics. Thus, in the long run, the outcome is the same regardless of the initial treatment. Notably, patients who initially received only APT or SMC were more likely to receive other subsequent treatments than other patients. In response to the investigators’ hypothesis that APT or SMC alone would promote benefits from other treatments (because they would be more likely than other patients to receive other subsequent treatments), which was not confirmed because there was no correlation between the patients’ physical improvement and whether or not they received subsequent treatments, Dr. Steven interpreted the results of the trial in the following way: The combination of structured CBT and GET was better than the combination of SMC or SMC combined with APT or SMC, and the results of the study were similar. SMC or SMC combined with APT promoted faster improvement of self-limiting symptoms in patients with chronic fatigue syndrome, an important finding for a disease with fewer treatments and a very low substantial mortality rate. Getting to the bottom of it, why do these treatments improve symptoms? Chronic fatigue syndrome is not well conceptualized and there is a clear intersection with neuropsychiatric disorders, such as depression. Pathophysiologic theories of chronic fatigue syndrome can be divided into contributing factors and neurobiologic symptoms. Hypothesized contributing factors may include: infections, environmental exposures, displacement of normal gut parasites, allergies, and physical and psychosocial stress. These factors could theoretically be involved in a large number of neurobiological processes in neuropsychiatric disorders, including neuroendocrinology, neurotransmission, neural shaping, oxidative and nitrosative stress regulation, mitochondrial function, and neuroimmunity. As more research has been conducted in neuroimmunity, researchers have found that chronic fatigue syndrome is associated with increased concentrations of proinflammatory cytokines, oxidative stress, and activated Toll-like receptors. Single nucleotide receptor polymorphisms have been found in patient genes that can affect complement cascades, cytokines, and Toll-like receptor signaling. In a 2014 neuroimaging study of patients with chronic fatigue syndrome, researchers used positron imaging to capture evidence of neuroinflammation as neuropsychiatric symptoms worsened. These neuroimmunologic studies can help clinicians better understand the effectiveness of PACE trial treatments as well as some new interventions. For example, exercise therapy may be promoting neurologic recovery through anti-inflammatory and antioxidant effects, and CBT has been noted to have anti-inflammatory effects. A deeper understanding of the pathophysiologic mechanisms of chronic fatigue syndrome can facilitate the generation of new diagnostic and therapeutic approaches. An early example of this is the discovery of rituximab (Merovia) for the treatment of chronic fatigue syndrome, for which a randomized controlled trial is currently underway. For many neuropsychiatric disorders, the discovery of new treatments such as these has been rare over the past few decades. Emerging evidence that mechanism-specific therapeutic measures, such as antioxidant and anti-inflammatory substances, have demonstrated significant effects in different neuropsychiatric disorders amply demonstrates the potential of this approach.