Major depressive disorder: probiotics may be an adjuvant therapy. Logan AC, Katzman M.

Source Nutrition Research Consulting, 50 Yonkers Terrace, 8-J Yonkers, NY 10704, USA. aclnd@cfs-fm.org Abstract Major depressive disorder (MDD) is an extremely complex and heterogeneous condition. Emerging research suggests that nutritional influences on MDD are currently underestimated. MDD patients have been shown to have elevated levels of pro-inflammatory cytokines, increased oxidative stress, altered gastrointestinal (GI) function, and lowered micronutrient and omega-3 fatty acid status. Small intestinal bacterial overgrowth (SIBO) is likely contributing to the limited nutrient absorption in MDD. Stress, a significant factor in MDD, is known to alter GI microflora, lowering levels of lactobacilli and bifidobacterium. Research suggests that bacteria in the GI tract can communicate with the central nervous system, even in the absence of an immune response. Probiotics have the potential to lower systemic inflammatory cytokines, decrease oxidative stress, improve nutritional status, and correct SIBO. The effect of probiotics on systemic inflammatory cytokines and oxidative stress may ultimately lead to increased brain derived neurotrophic factor (BDNF). It is our contention that probiotics may be an adjuvant to standard care in MDD. PMID: 15617861 [PubMed - indexed for MEDLINE]

Comparison of oral nicotinamide adenine dinucleotide (NADH) versus conventional therapy for chronic fatigue syndrome. Santaella ML, Font I, Disdier OM. Source Department of Medicine, University of Puerto Rico School of Medicine, Medical Sciences Campus, San Juan, Puerto Rico. Abstract OBJECTIVE: To compare effectiveness of oral therapy with reduced nicotinamide adenine dinucleotide (NADH) to conventional modalities of treatment in patients with chronic fatigue syndrome (CFS). BACKGROUND:

CFS is a potentially disabling condition of unknown etiology. Although its clinical presentation is associated to a myriad of symptoms, fatigue is a universal and essential finding for its diagnosis. No therapeutic regimen has proven effective for this condition. METHODS: A total of 31 patients fulfilling the Centers for Disease Control criteria for CFS, were randomly assigned to either NADH or nutritional supplements and psychological therapy for 24 months. A thorough medical history, physical examination and completion of a questionnaire on the severity of fatigue and other symptoms were performed each trimester of therapy. In addition, all of them underwent evaluation in terms of immunological parameters and viral antibody titers. Statistical analysis was applied to the demographic data, as well as to symptoms scores at baseline and at each trimester of therapy. RESULTS: The twelve patients who received NADH had a dramatic and statistically significant reduction of the mean symptom score in the first trimester (p < 0.001). However, symptom scores in the subsequent trimesters of therapy were similar in both treatment groups. Elevated IgG and Ig E antibody levels were found in a significant number of patients. CONCLUSIONS: Observed effectiveness of NADH over conventional treatment in the first trimester of the trial and the trend of improvement of that modality in the subsequent trimesters should be further assessed in a larger patient sample. PMID: 15377055 [PubMed - indexed for MEDLINE] Unproven diet therapies in the treatment of the chronic fatigue syndrome. Morris DH, Stare FJ. Source Department of Nutrition, Harvard School of Public Health, Boston, Mass. Abstract This report is a review of the unproven diet therapies recommended for individuals with chronic fatigue syndrome (CFS). Diet therapies promoted for the relief of CFS symptoms by the authors of five CSF self-help books were evaluated on the basis of nutritional adequacy and scientific rationale. Unproven diet therapies for patients with CFS include megavitamin/mineral supplements; royal jelly and other dietary supplements; and elimination, avoidance, and rotation diets. Claims that these therapies relieve CFS

symptoms and promote recovery are anecdotal and have not been substantiated by clinical research. The yeast-avoidance and sugar-free diets, both promoted to combat Candida albicans overgrowth, are of questionable value in treating patients with CFS. The rotation diet is not balanced and does not meet the current recommended dietary intake levels. Diet strategies that call for the avoidance of food additives, preservatives, sweeteners, and other ingredients are not supported by available evidence and are not practical for patients with CFS. A diet plan for patients with CFS should be based on sound nutritional principles and common sense. Until the results of studies demonstrating the benefits of particular diet therapies in the management of CFS are available, patients with CFS are advised to eat a varied diet selected from among and within the basic food groups to ensure an adequate nutrient intake and to reach and maintain a reasonable body weight.

J R Soc Med. 1999 Apr;92(4):183-5. Vitamin B status in patients with chronic fatigue syndrome. Heap LC, Peters TJ, Wessely S. Source Department of Clinical Biochemistry, King's College School of Medicine, London, UK. Abstract Some patients with chronic fatigue syndrome say they benefit from taking vitamin supplements. We assessed functional status for the B vitamins pyridoxine, riboflavin and thiamine in 12 vitamin-untreated CFS patients and in 18 healthy controls matched for age and sex. Vitamin-dependent activities--aspartate aminotransferase (AST) for pyridoxine, glutathione reductase (GTR) for riboflavin, transketolase (TK) for thiamine--were measured in erythrocyte haemolysates before and after in-vitro addition of the relevant vitamin. For all three enzymes basal activity (U/g Hb) was lower in CFS patients than in controls: AST 2.84 (SD 0.62) vs 4.61 (1.43), P < 0.001; GTR 6.13 (1.89) vs 7.42 (1.25), P < 0.04; TK 0.50 (0.13) vs 0.60 (0.07), P < 0.04. This was also true of activated values: AST 4.91 (0.54) vs 7.89 (2.11), P < 0.001; GTR 8.29 (1.60) vs 10.0 (1.80), P < 0.001; TK 0.56 (0.19) vs 0.66 (0.08), P < 0.07. The activation ratios, however, did not differ between the groups. These data provide preliminary evidence of reduced functional B vitamin status, particularly of pyridoxine, in CFS patients. PMID: 10450194 [PubMed - indexed for MEDLINE] PMCID: PMC1297139 Fr

Altern Med Rev. 2000 Apr;5(2):93-108.

Nutritional strategies for treating chronic fatigue syndrome. Werbach MR. Source UCLA School of Medicine, California, USA. Abstract Despite considerable worldwide efforts, no single etiology has been identified to explain the development of chronic fatigue syndrome (CFS). It is likely that multiple factors promote its development, sometimes with the same factors both causing and being caused by the syndrome. A detailed review of the literature suggests a number of marginal nutritional deficiencies may have etiologic relevance. These include deficiencies of various B vitamins, vitamin C, magnesium, sodium, zinc, L-tryptophan, Lcarnitine, coenzyme Q10, and essential fatty acids. Any of these nutrients could be marginally deficient in CFS patients, a finding that appears to be primarily due to the illness process rather than to inadequate diets. It is likely that marginal deficiencies not only contribute to the clinical manifestations of the syndrome, but also are detrimental to the healing processes. Therefore, when feasible, objective testing should identify them and their resolution should be assured by repeat testing following initiation of treatment. Moreover, because of the rarity of serious adverse reactions, the difficulty in ruling out marginal deficiencies, and because some of the therapeutic benefits of nutritional supplements appear to be due to pharmacologic effects, it seems rational to consider supplementing CFS patients with the nutrients discussed above, along with a general highpotency vitamin/mineral supplement, at least for a trial period. Comment in The following popper user interface control may not be accessible. Tab to the next button to revert the control to an accessible version.Destroy user interface controlNutritional strategies for treating chronic fatigue syndrome. [Altern Med Rev. 2001]

nt J Tryptophan Res. 2012;5:27-32. doi: 10.4137/IJTR.S10085. Epub 2012 Sep 17. A Brief Historic Overview of Clinical Disorders Associated with Tryptophan: The Relevance to Chronic Fatigue Syndrome (CFS) and Fibromyalgia (FM). Blankfield A. Source Kew, Australia.

Abstract Last century there was a short burst of interest in the tryptophan related disorders of pellagra and related abnormalities that are usually presented in infancy.1,2 Nutritional physiologists recognized that a severe human dietary deficiency of either tryptophan or the B group vitamins could result in central nervous system (CNS) sequelae such as ataxia, cognitive dysfunction and dysphoria, accompanied by skin hyperpigmentation.3,4 The current paper will focus on the emerging role of tryptophan in chronic fatigue syndrome (CFS) and fibromyalgia (FM). PMID: 23032646 [PubMed] PMCID: PMC3460668 Free PMC Article The following toggler user interface control may not be accessible. Tab to the next button to revert the control to an accessible version.Destroy user interface control LinkOut - more resources

Int J Tryptophan Res. 2012; 5: 2732. Published online 2012 September 17. doi: 10.4137/IJTR.S10085 PMCID: PMC3460668 A Brief Historic Overview of Clinical Disorders Associated with Tryptophan: The Relevance to Chronic Fatigue Syndrome (CFS) and Fibromyalgia (FM)

Adele Blankfield Author information Copyright and License information Go to: Abstract Last century there was a short burst of interest in the tryptophan related disorders of pellagra and related abnormalities that are usually presented in infancy.1,2 Nutritional physiologists recognized that a severe human dietary deficiency of either tryptophan or the B group vitamins could result in central nervous system (CNS) sequelae such as ataxia, cognitive dysfunction and dysphoria, accompanied by skin hyperpigmentation.3,4 The current paper will focus on the emerging role of tryptophan in chronic fatigue syndrome (CFS) and fibromyalgia (FM).

Keywords: tryptophan, pellagra, gamma interferon, chronic fatigue syndrome, fibromyalgia, vitamin B12

Go to: Tryptophan Metabolism Until the year 2000, research into the specific attributes of the serotonin pathway and its role in neuro-psychiatric disorders disorders was double that of other aspects of tryptophan metabolism.5 Experimental tryptophan depletion tests were devised to ascertain the influence of serotonin metabolism on cognition, mood and behavior. 57 Brief tryptophan depletion tests in normal human subjects, for example, provided consistent evidence for its role in impaired memory consolidation and reduced visual perception.7,8 Older studies of prolonged dietary depletion of both tryptophan and niacin were known to lead to severe pellagra, with neurological and extensive inflammatory mucosal membrane changes. These occurred within one to two months of a depleted diet.9 In recent decades, however, the involvement of this essential amino acid in the kynurenine pathway has been elucidated.5,10 This has in part explained some of the pathological processes of pellagra.

Protein catabolism had long been recognized as the big picture metabolic response to all noxious bodily stimuli such as trauma, infection and neoplastic processes. Upon further analysis of the separate amino-acid constituents of proteins, the degradation of tryptophan emerged as a major contributor to the catabolic process,7,1014 amongst its other critical functions such as neuromodulation. The intimate relationship in the kynurenine pathway between tryptophan, gamma-interferon and 2-3dioxygenase (IDO) as an immuno-modulatory mechanism has since been substantiated. 10,15 The kynurenine pathway is also linked to the synthesis of nicotinamide adenine dinucleotide (NAD) from quinolinic acid, and it is up-regulated by neurodegenerative and other inflammatory triggers. 10 This discovery of the existence of two tryptophan metabolic pathways in the CNS and peripheral nervous system has challenged researchers to discriminate between the consequences activation of these dual paths.1014

There have been subsequent advances in technologies, such as developments in magnetic resonance imaging (MRI) and positron emission tomography (PET),16 as well as an increased range of available biochemical and genetic tests.10 These newer techniques have generated data from specialist molecular biologists at cellular and micrometabolic levels. This sophisticated phase of research has increased our understanding of the physiological mechanisms that underpin basic principles and observations in medicine. The information is extremely complex, and there tends to be a time lag before it is incorporated into clinical application.

Go to: Some Clinical Disorders The gastrointestinal tract is the nutrient gateway to the body and little is known about tryptophan activity in this area. The combination of malnutrition, malabsorption and metabolic inefficiencies is difficult to unravel. Resultant physical defects from tryptophan depletion can range from mild to severe and can be hard to detect and interpret.17,18

Tryptophan absorption1922 and metabolic utilization23 are vulnerable to both primary inborn genetic errors and secondary gut disturbances. In addition, there are several inherited autoimmune diseases of the bowel that affect absorption, such as celiac and Crohns disease.5,17,18 These conditions usually do not become apparent until adulthood. Case reports of intestinal autoantibodies to tryptophan hydroxylase have occurred in adults, associated with bowel dysfunction and other systemic autoimmune disorders.2427 At the present time, these various conditions are not completely understood.

Rose1 (1972) outlined the clinical issues of that era. He also detailed three inborn errors including Hartnup Disease, hypertryptophanemia and 3hydroxy- kynureninuria. Sabator and Ricos28 reported the presence of kynurenine irregularities in 5% of 830 institutionalized children with mental retardation. Other primary abnormalities of childhood29 33 including tryptophanol glycine absorption disorder23 have subsequently been documented.

Hartnup Disease is an autosomal recessive condition that is no longer included in neonatal screening programs.34,35 This disease is thought to have the same community prevalence as phenylketonuria. It is noted for its clinical variability and onset can occur in adulthood. The physical phenomena resembling pellagra36 in Hartnups Disease responds to treatment with either nicotinamide or neomycin. Carcinoid tumours,2 drug side effects,37 and nutritional inadequacies can also present with secondary pellagrous states.4

Go to: The Relevance of Tryptophan to CFS/FM The potential connection between the kynurenine pathway and CFS was initially made in 199138 and with FM in 1993.39 This hypothesis was

recently revived as more evidence of tryptophan pathway dysfunction in CFS/FM has since accrued.40,41 CFS/ FM could involve serum tryptophan level deficiency, 42,43 and impaired immune-modulatory function has been demonstrated at the gamma-interferon, IDO stage of metabolism.38,44 In addition, there appears to be some resemblance between CFS/FM irregularities and those found in other medical conditions.45,46

Go to: Clinical Outline CFS/FM constitutes a definite single syndrome. There is a consistent, recurring pattern of core symptoms in affected populations.4749 Some physicians prefer the hybrid classification of overlap syndrome, whereas a few patient support groups opt for the term myalgic encephalomyelitis (ME). The differences lie in theoretical explanatory constructs. Uncertain fluctuations in the course and outcomes of individual patients confound some aspects of scientific analysis.

The signs and symptoms of the condition are well documented in the specialist CFS/FM literature.4749 Patients present with extreme exhaustion, which is aggravated by exertion and altered sleep patterns. Concentration and memory is impoverished45,50,51 and patients experience visual disturbances48,49 and unfathomable pain.5,48,49 They may suffer inexplicable gastrointestinal and urogenital tract discomforts.27,52,53 Amongst less obvious symptoms are ataxia, myopathy, lowered thyroid and cortisol levels, food intolerances and puzzling skin conditions.4749

Go to: Tryptophan Status in CFS/FM In 1975, Moldofsky and colleagues54 looked to serotonin in an attempt to explain the nonrestorative sleep syndrome of fibrositis (later termed fibromyalgia). In a 1978 study, patients tryptophan levels were noted to be lowered.42 This observation was repeated by Yunus and colleagues55 in 1992. The extensive studies of Russell and colleagues39 were undervalued at that time. Russel and colleagues discovered an abnormality in the conversion stage of 3-hydroxy kynurenine in the CNS in FM patients.39,48 Since then, research into the attributes of tryptophan in the context of CFS/FM has continued.42,43,56,57 A couple of subsequent studies examined amino acid urinary profiles and other biochemical parameters in CFS patients and controls, without specific mention of tryptophan.58,59

There are several possible explanations for the observed decrease in tryptophan levels in CFS/FM patients. This decrease may be due to any primary genetic disorder, or may be due to malabsorptions created by an idiopathic irritable bowel syndrome,52,53 food intolerances, bacterial overgrowth and other bowel disorders.16,17 Silent or chronic infections can increase metabolic demands for tryptophan and vitamin B12. Nicotinamide absorption can be reduced through severe diarrhea. These listed observations imply that tryptophan, nicotinamide and B12 deficiencies can become a complication of CFS/FM.40,42,6063 Evidence for the requirement of L-carnitine, zinc42 and intravenous vitamin solutions64 is circumstantial. This question of nutrient substrate deficiency warrants investigation along formal medical protocols rather than the less structured methods of complementary and alternative medicine models. It is also important to establish if there is a point at which the decline in available metabolic fuel reaches a critical level and structural morphological damage becomes irreversible, leading to chronically impaired health.

Go to: Gamma-Interferon and Other Immune Dysfunctions CFS/FM has, in part, been recognized as an immune deficiency syndrome.4749,65 Bell47 was at a loss to explain the immunological profile of the CFS/FM patient; however, he appreciated that it was still early days in the field of cytokine research. He divided the observed irregularities into categories, based on either overactivity or underactivity of the immune system. Underactivity was reflected in a decreased number and function of natural killer cells,6567 a decreased mitogen response and decreased antibody levels, particularly in the IgG subclasses, in response to infections. In contrast, up-regulation or overactivity of the immune system involved elevated levels of gamma-interferon and other cytokines. CD8 lymphocytes might increase in number with a consequent effect on the CD4:CD8 ratio. Multiple allergies (atopy)68 and autoantibody production could be activated. He later considered whether the prolonged malaise observed in CFS could be due to the persistence of infection caused by impaired patient immunity.65 He suggested that another factor might involve failure of an initial immune defense response by the host, leading the host to shut down and therefore be unable to proceed along the pathway of resolution.

Lloyd and colleagues67 had already documented aspects of disordered immune regulation in 1989 in their CFS patients. They discovered that this abnormality related to the host response and could not be attributed to any specific viral infectious agent. They were aware that the therapeutic use of interferons in other medical conditions could produce severe CFS-like

symptoms as a side effect.69 They anticipated that gamma-interferon would be implicated in CFS illness complications.

Kerr and colleagues44 performed extensive studies of patients infected with parvovirus 19. They detected the continued presence of the alpha-tumor necrosis factor and gamma-interferon in both the acute and convalescent phases of this infection. They associated these anomalies with the prolongation of a fatigued state. Kerr and his co-workers were amongst those researchers who proposed that immune control of the virus may not be efficient. 67,7073 This feature might, in addition, explain the presence of under-recognized neuropathic pain of subclinical Zoster sine Herpete74 and of any other infectious and avitaminotic states in CFS/FM patients.4,5

Go to: Conclusion Contemporary tryptophan research examines the up-regulation of the kynurenine pathway by neurological and psychiatric disorders and autoimmune, neoplastic and infectious diseases. The ultimate aims of these studies are to further the understanding of the neurological consequences of these illnesses and to improve their treatment prospects.7,1014

There are comparative clusters of signs and symptoms in both patients with CFS/FM and in those whose conditions relate predominantly to the kynurenine pathway. Thus, CFS/FM patients could benefit from investigations searching for primary errors of tryptophan metabolism and other kynurenine pathway pathologies.10,34,60

In 1986, Mersky75 stated that a lack of adequate technology and a proper unwillingness to undertake hazardous investigations for obscure symptoms may encourage a false attribution of psychological symptoms to physical illness. He listed examples of some conditions that had been reclassified as organic in nature. He recommended that the diagnostic status of the patient be reviewed if warranted.

Go to: Footnotes Author Contributions

Wrote the first draft of the manuscript: AB. Contributed to the writing of the manuscript: AB. Jointly developed the structure and arguments for the paper: AB. Made critical revisions and approved final version: AB. All authors reviewed and approved of the final manuscript.

Competing Interests

Author(s) disclose no potential conflicts of interest.

Disclosures and Ethics

As a requirement of publication author(s) have provided to the publisher signed confirmation of compliance with legal and ethical obligations including but not limited to the following: authorship and contributorship, conflicts of interest, privacy and confidentiality and (where applicable) protection of human and animal research subjects. The authors have read and confirmed their agreement with the ICMJE authorship and conflict of interest criteria. The authors have also confirmed that this article is unique and not under consideration or published in any other publication, and that they have permission from rights holders to reproduce any copyrighted material. Any disclosures are made in this section. The external blind peer reviewers report no conflicts of interest.

Funding

Author(s) disclose no funding sources.

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27. Tack J, Janssen P, Wouters M, Boeckxstaens G. Targeting serotonin synthesis to treat irritable bowel syndrome. Gastroenterology. 2011;141(2):4202. [PubMed] 28. Sabater J, Rics C. Abnormalities of tryptophan metabolism (kynurenine pathway) found in a group of 830 mentally retarded children. Clin Chem Acta. 1974;56(2):17586. [PubMed] 29. Heely AF, Heeley ME, Hardy J, Soothill JF. A disorder of tryptophan metabolism in chronic granulomatous disease. Arch Dis Child. 1970;45(242):48590. [PMC free article] [PubMed] 30. Salih MA, Bender DA, McCreanor GM. Lethal familial pellagra-like skin lesion associated with neurologic and developmental impairment and the development of cataracts. Pediatrics. 1985;76(5):78793. [PubMed] 31. Assmann B. Biogenic amines and pterins in cerebrospinal fluid: some pitfalls with interpretation. Future Neurol. 2006;1(5):6517. 32. Hyland K. Inherited disorders affecting dopamine and serotonin: critical neurotransmitters derived from aromatic amino acids. J Nutr. 2007;137(6 Suppl 1):1568S72. [PubMed] 33. Schott DA, Nicolas J, de Vries JE, Keularts IM, Rubio-Gozalbo ME, Gerver WJ. Disorder in the serotonergic system due to tryptophan hydroxylation impairment: a cause of hypothalamic syndrome? Horm Res Paediatr. 2010;73(1):6873. [PubMed] 34. Wilken B, Yu JS, Brown DA. Natural History of Hartnup Disease. Arch Dis Child. 1977;52(1):3840. [PMC free article] [PubMed] 35. Seow HF, Brer S, Brer A, et al. Hartnup disorder is caused by mutations in the gene encoding the neutral amino acid transporter SLC 6A19. Nature Genetics. 2004;36(9):10037. [PubMed] 36. Oakley A, Wallace J. Hartnup disease presenting in an adult. Clin Exp Dermatol. 1994;19(5):4078. [PubMed] 37. Poaletti R, Sirtori C, Jr, Spano PF. Clinical relevance of drugs affecting tryptophan transport. Annu Rev Pharmacol. 1975;15:7381. [PubMed] 38. Fuchs D, Weiss G, Wachter H. Pathogenesis of chronic fatigue syndrome. J Clin Psychiatry. 1992;53(8):296. [PubMed] 39. Russell IJ, Vipraio GA, Acworth J. Abnormalities in the central nervous (CNS) metabolism of tryptophan (TRY) to 3-hydroxy kynurenine (OHKY) in fibromyalgia syndrome (FS) Arthritis Rheum. 1993;36(9):S222. 40. Blankfield A. Kynurenine pathway hypothesis: The nature of the Chronic Fatigue Syndrome (CFS) Revisited. Int J Tryptophan Res. 2011;4:478. [PMC free article] [PubMed]

41. Popper Karl R. The growth of scientific knowledge. London: Routledge and Kegan Paul; 1972. Conjectures and Refutations. 42. Werbach MR. Nutritional strategies for treating chronic fatigue syndrome. Altern Med Rev. 2000;5(2):93108. [PubMed] 43. Werbach MR. Serotonin in chronic fatigue syndrome and fibromyalgia. Townsend letter for doctors and patients. 2001 Nov; 44. Kerr JR, Barah F, Mattey DL, et al. Circulating tumour necrosis factoralpha and interferon-gamma are detectable during acute and convalescent parvovirus B19 infection and are associated with prolonged and chronic fatigue. J Gen Virol. 2001;82(Pt 12):30119. [PubMed] 45. Constant EL, Adam S, Gillain B, Lambert M, Masquellier E, Seron X. Cognitive deficits in patients with chronic fatigue syndrome compared to those with major depressive disorder and healthy controls. Clin Neurol Neurosurg. 2011;113(4):295302. [PubMed] 46. Hickie I, Lloyd A, Wakefield D, Parker G. The psychiatric status of patients with the chronic fatigue syndrome. Brit J Psychiat. 1990;156:534 40. [PubMed] 47. Bell David S. The Doctors Guide to Chronic Fatigue Syndrome. Boston: Addison-Wesley Publishing Company; 1995. 48. Russell IJ. J of Musculoskeletal Pain. 4. Vol. 11. Binghampton: Haworth Medical Press; 2003. 2003. The fibromyalgia syndrome: A clinical case definition for practitioners. 49. Carruthers BM, van de Sande M. Myalgic encephalomyelitis/chronic fatigue syndrome: A clinical case definition and guidelines for medical practitioners. A consensus document. JCFS. 2003;11(1):7115. 50. Park DC, Glass IM, Minear M, Crofford J. Cognitive Function in fibromyalgia patients. Arthritis Rheum. 2001;44(9):212533. [PubMed] 51. Rodrguez-Andreu J, Ibnez-Bosch R, Portero-Vzquez A, Masramon X, Rejas J, Glvez R. Cognitive impairment in patients with fibromyalgia syndrome as assessed by the mini-mental state examination. BMC Musculoskelet Disord. 2009;10:162. [PMC free article] [PubMed] 52. Nickel JC, Tripp DA, Pontari M, et al. Interstitial cystitis/painful bladder syndrome and associated medical conditions with an emphasis on irritable bowel syndrome, fibromyalgia and chronic fatigue syndrome. J Urol. 2010;184(4):135863. [PubMed] 53. Clarke G, McKernan DP, Gaszner G, et al. A distinct profile of tryptophan metabolism along the kynurenine pathway downstream of toll-like receptor activation in irritable bowel syndrome. Front Pharmacol. 2012;3:90. [PMC free article] [PubMed]

54. Moldofsky H, Scarisbrick P, England R, Smythe H. Musculoskeletal symptoms and non-REM sleep disturbances in patients with fibrositis syndrome and healthy subjects. Psychosom Med. 1975;37(4):34151. [PubMed] 55. Yunus MB, Dailey JW, Aldag JC, Masi AT, Jobe PC. Plasma tryptophan and other amino acids in primary fibromyalgia: a controlled study. J Rheumatol. 1992;19(1):904. [PubMed] 56. Schwartz MJ, Offenbaecher M, Neumeister A, Ackenheil M. Experimental evaluation of an altered tryptophan metabolism in fibromyalgia. In: Allegri G, Costa CVL, Ragazzi E, Steinhart H, Laresio L, editors. Developments in Tryptophan and Serotonin Metabolism. New York: Kluwer Academic/Plenum Publishers; 2003. 57. Bazzichi L, Palego L, Giannaccini G, et al. Altered amino acid homeostasis in subjects affected by fibromyalgia. Clin Biochem. 2009;42(1011):106470. [PubMed] 58. Jones MG, Cooper Amjad S, Goodwin CS, Barron JL, Chalmers RA. Urinary and plasma organic acids and amino acids in chronic fatigue syndrome. Clin Chem Acta. 2005;361:1508. [PubMed] 59. Niblett SH, King KE, Dunstan RH, et al. Hematologic and urinary excretion anomalies in patients with chronic fatigue syndrome. Exp Biol Med ( Maywood) 2007;232(8):10419. [PubMed] 60. Belensky P, Bogan KL, Brenner C. NAD+ metabolism in health and disease. Trends Biochem Sci. 2007;32(1):129. [PubMed] 61. Murray MF. Nicotinamide: an oral antimicrobial agent with activity against both Mycobacterium tuberculosis and human immunodeficiency virus. Clin Infect Dis. 2003;36(4):45360. [PubMed] 62. Regland G, Andersson M, Abrahamsson L, Bagby J, Dyrehag LE, Gottfries CG. Increased concentrations of homocystine in the cerebrospinal fluid in patients with fibromyalgia and chronic fatigue syndrome. Scand J Rheumatol. 1997;26(4):3017. [PubMed] 63. Ortancil O, Sanli A, Eryuksel R, Basaran A, Ankarali H. Association between serum ferritin level and fibromyalgia syndrome. Eur J Clin Nutr. 2010;64(3):30812. [PubMed] 64. Ali A, Njike VY, Northrup V, et al. Intravenous micronutrient therapy [Myers Cocktail] for fibromyalgia: a placebo-controlled pilot study. J Altern Complement Med. 2009;15(3):24757. [PMC free article] [PubMed] 65. Bell David S. Cellular Hypoxia and Neuro-immune Fatigue. Livermore: Wingspan Press; 2007.

66. Brenu EW, van Driel ML, Staines DR, et al. Immunological abnormalities as potential biomarkers in chronic fatigue syndrome/myalgic encephalomyelitis. J Translational Medicine. 2011;9:81. [PMC free article] [PubMed] 67. Lloyd AR, Wakefield D, Boughton CR, Dwyer JM. Immunological abnormalties in the chronic fatigue syndrome. Med J Aust. 1989;151(3):122 4. [PubMed] 68. von Bubnoff D, Hanau D, Wenzel J, et al. Indoleamine 2, 3-dioxygenase expressing antigen presenting cells and peripheral T-cell tolerance: another piece to the atopic puzzle? J Allergy Clin Immunol. 2003;112(5):85460. [PubMed] 69. Vial T, Descotes J. Clinical toxicity of the interferons. Drug SAF. 1994;10(2):11550. [PubMed] 70. Kerr JR, Gough J, Richards SC, et al. Antibody to parvovirus B19 nonstructural protein is associated with chronic arthralgia in patients with chronic fatigue syndrome/myalgic encephalomyelitis. J Gen Virol. 2010;91(Pt 4):8937. [PubMed] 71. Bansal AS, Bradley AS, Bishop KN, Kiani-Alikhan S, Ford B. Chronic fatigue syndrome, the immune system and viral infection. Brain Behave Immun. 2012;26(1):2431. [PubMed] 72. Meeus M, Mistiaen W, Lampbrecht L, Nijs J. Immunological similarities between cancer and chronic fatigue syndrome: the common link to fatigue? Anticancer Res. 2009;29(11):471726. [PubMed] 73. Dubener W, Mackenzie CR. IFN-gamma activated indoleamine 2,3dixoygenase activity in human cells is an antiparasitic and an antibacterial effector mechanism. Adv Exp Med Biol. 1999;467:51724. [PubMed] 74. Shapiro JS. Does varicella-zoster virus infection of the peripheral ganglia cause Chronic Fatigue Syndrome? Med Hypotheses. 2009;73(5):72834. [PubMed] 75. Mersky H. The importance of hysteria. Br J Psychiatry. 1986;149:238. [PubMed] Articles from International Journal of Tryptophan Research : IJTR are provided here courtesy of Libertas Academica

Curr Pharm Des. 2008;14(13):1274-94. Central nervous system abnormalities in fibromyalgia and chronic fatigue syndrome: new concepts in treatment. Gur A, Oktayoglu P.

Source Department of Physical Medicine and Rehabilitation, Medical Faculty, Dicle University, 21280 Diyarbakir, Turkey. alig@dicle.edu.tr Abstract Fibromyalgia (FM) and chronic fatigue syndrome (CFS) are poorly understood disorders that share similar demographic and clinical characteristics. The etiology and pathophysiology of these diseases remain unclear. Because of the similarities between both disorders it was suggested that they share a common pathophysiological mechanisms, namely, central nervous system (CNS) dysfunction. Current hypotheses center on atypical sensory processing in the CNS and dysfunction of skeletal muscle nociception and the hypothalamic-pituitary-adrenal (HPA) axis. Researches suggest that the (CNS) is primarily involved in both disorders in regard to the pain, fatigue and sleep disturbances. Many patients experience difficulty with concentration and memory and many others have mood disturbance, including depression and anxiety. Although fibromyalgia is common and associated with substantial morbidity and disability, there are no US Food and Drug Administration (FDA)-approved treatments except pregabalin. Recent pharmacological treatment studies about fibromyalgia have focused on selective serotonin and norepinephrine (NE) reuptake inhibitors, which enhance serotonin and NE neurotransmission in the descending pain pathways and lack many of the adverse side effects associated with tricyclic medications. CFS is a descriptive term used to define a recognisable pattern of symptoms that cannot be attributed to any alternative condition. The symptoms are currently believed to be the result of disturbed brain function. To date, no pharmacological agent has been reliably shown to be effective treatment for CFS. Management strategies are therefore primarily directed at relief of symptoms and minimising impediments to recovery. This chapter presents data demonstrating CFS, abnormal pain processing and autonomic nervous system (ANS) dysfunction in FM and CFS and concludes by reviewing the new concepts in treatments in CFS and FM.

Rheum Dis Clin North Am. 2000 Nov;26(4):989-1002. Neuroendocrine perturbations in fibromyalgia and chronic fatigue syndrome. Neeck G, Crofford LJ. Source Department of Rheumatology, University of Giessen, Bad Nauheim, Germany. gunther.neeck@kerckhoff.med.uni-giessen.de Abstract

A large body of data from a number of different laboratories worldwide has demonstrated a general tendency for reduced adrenocortical responsiveness in CFS. It is still not clear if this is secondary to CNS abnormalities leading to decreased activity of CRH- or AVP-producing hypothalamic neurons. Primary hypofunction of the CRH neurons has been described on the basis of genetic and environmental influences. Other pathways could secondarily influence HPA axis activity, however. For example, serotonergic and noradrenergic input acts to stimulate HPA axis activity. Deficient serotonergic activity in CFS has been suggested by some of the studies as reviewed here. In addition, hypofunction of sympathetic nervous system function has been described and could contribute to abnormalities of central components of the HPA axis. One could interpret the clinical trial of glucocorticoid replacement in patients with CFS as confirmation of adrenal insufficiency if one were convinced of a positive therapeutic effect. If patient symptoms were related to impaired activation of central components of the axis, replacing glucocorticoids would merely exacerbate symptoms caused by enhanced negative feedback. Further study of specific components of the HPA axis should ultimately clarify the reproducible abnormalities associated with a clinical picture of CFS. In contrast to CFS, the results of the different hormonal axes in FMS support the assumption that the distortion of the hormonal pattern observed can be attributed to hyperactivity of CRH neurons. This hyperactivity may be driven and sustained by stress exerted by chronic pain originating in the musculoskeletal system or by an alteration of the CNS mechanism of nociception. The elevated activity of CRH neurons also seems to cause alteration of the set point of other hormonal axes. In addition to its control of the adrenal hormones, CRH stimulates somatostatin secretion at the hypothalamic level, which, in turn, causes inhibition of growth hormone and thyroid-stimulating hormone at the pituitary level. The suppression of gonadal function may also be attributed to elevated CRH because of its ability to inhibit hypothalamic luteinizing hormone-releasing hormone release; however, a remote effect on the ovary by the inhibition of folliclestimulating hormone-stimulated estrogen production must also be considered. Serotonin (5-HT) precursors such as tryptophan (5-HTP), drugs that release 5-HT, or drugs that act directly on 5-HT receptors stimulate the HPA axis, indicating a stimulatory effect of serotonergic input on HPA axis function. Hyperfunction of the HPA axis could also reflect an elevated serotonergic tonus in the CNS of FMS patients. The authors conclude that the observed pattern of hormonal deviations in patients with FMS is a CNS adjustment to chronic pain and stress, constitutes a specific entity of FMS, and is primarily evoked by activated CRH neurons.

PMID: 11084955 [PubMed - indexed for MEDLINE]

The following toggler user interface control may not be accessible. Tab to the next button to revert the control to an accessible version.Destroy user interface control Publication Types, MeSH Terms, Grant Support The following toggler user interface control may not be accessible. Tab to the next button to revert the control to an accessible version.Destroy user interface control LinkOut - more resources

J Womens Health (Larchmt). 2010 May; 19(5): 951958. doi: 10.1089/jwh.2009.1697 PMCID: PMC2875960 Sex Differences in Plasma Prolactin Response to Tryptophan in Chronic Fatigue Syndrome Patients With and Without Comorbid Fibromyalgia

Shelley A. Weaver, Ph.D.,1 Malvin N. Janal, Ph.D.,2,,3 Nadine Aktan, Ph.D., A.P.N.,1,,3 John E. Ottenweller, Ph.D.,1,,3 and Benjamin H. Natelson, M.D.1,,3 Author information Copyright and License information Go to: Abstract Background

Some think chronic fatigue syndrome (CFS) and fibromyalgia (FM) are variants of the same illness process. This would imply that CFS patients with and without comorbid FM have similar biological underpinnings. To test this, we compared serotonergic-based responses, plasma prolactin (PRL), and self-reported measures of fatigue to intravenous infusion of tryptophan among patients with CFS alone, CFS+FM, and healthy controls.

Methods

Men and women with CFS alone or CFS+FM and healthy subjects, none with current major depressive disorder (MDD), were given 120mg of l-tryptophan

per kg lean body mass intravenously (i.v.). Before and after tryptophan infusion, blood samples were collected, and plasma PRL, tryptophan, and kynurenine concentrations were determined.

Results

Women with CFS alone, but not CFS+FM, showed upregulated plasma PRL responses compared with controls. There were no differences among groups of men. Plasma tryptophan and kynurenine concentrations did not differ among groups.

Conclusions

These results indicate that women with CFS alone have upregulated serotonergic tone that is not seen in those with comorbid FM. The lack of effect in men suggests a mechanism that might explain, in part, the increased prevalence of CFS in women. The data support the interpretation that CFS in women is a different illness from FM.

Go to: Introduction Chronic fatigue syndrome (CFS) and fibromyalgia (FM) are medically unexplained illnesses predominantly affecting women.1 The hallmark symptom of CFS is debilitating fatigue, which is accompanied by such symptoms as impaired concentration, headaches, unrefreshing sleep, and muscle/joint pain.2 When muscle and joint pain are widespread and tender points are frequent, patients can fulfill the case definition for FM as well3; 37% of women with CFS in our Pain & Fatigue Center also fulfilled criteria for FM.4 There is a good deal of overlap between the symptoms of these two syndromes, and controversy exists about whether these are two distinct disorders or simply variants along a spectrum of a single illness.5

The symptoms of fatigue and widespread pain suggest a central nervous system (CNS) origin for FM and CFS. The neurotransmitter serotonin (5-HT) plays a role in both fatigue and pain sensitivity; therefore, 5-HT has been implicated in the symptomatology of both FM and CFS.6 For example, when brain 5-HT is increased either by exercise or administration of the 5-HT precursor tryptophan, fatigue follows.710 Importantly however, under

these conditions, pain sensitivity decreases, and in contrast, pain sensitivity increases when levels of brain 5-HT are low.1012 That fatigue follows an upregulated system whereas pain follows a downregulated system suggests pathophysiological differences between syndromes of severe fatigue and widespread pain with tendernessCFS and FM, respectively.

Researchers have used a variety of pharmacological probes to test serotonergic tone in CFS patients. Some studies suggest increased serotonergic tone via increased release of 5-HT and upregulated postsynaptic receptor levels,1316 whereas others have reported no evidence for altered 5-HT in CFS.1719 Only one study has focused on FM, and it too reported increases.20 This unexpected result may have stemmed from the use of buspirone as probe, which also targets dopaminergic receptors. This lack of specificity may also explain, in part, the variable result in CFS.

Another important possible reason for these inconsistencies stems from the fact that previous studies of central 5-HT in CFS and in FM have not specified whether their patient populations comprised patients with CFS or FM alone or patients having both diagnoses. Therefore, the studies done to date have likely involved heterogeneous populations with unknown proportions of those with CFS+FM vs. CFS or FM alone. Despite its syndromic overlap with CFS, FM is proposed to have the opposite serotonergic regulation from CFS, namely, deficient central 5-HT signaling2123; therefore, the presence of comorbid FM may have confounded the results of previous studies of central 5-HT in CFS patients.

5-HT is synthesized from the amino acid tryptophan via the enzyme tryptophan hydroxylase, which is not normally saturated with tryptophan. As a result, tryptophan loading increases tryptophan concentrations and 5-HT synthesis in the brain in humans24,25 as well as animals.26,27 In fact, tryptophan can be considered a highly specific 5-HT probe, and its effects are not limited to the increased activation of a few select 5-HT receptor subtypes. To date, tryptophan has not been used to probe the serotonergic system in CFS patients.

The major objective of this study was to assess brain serotonergic activity indirectly via plasma prolactin (PRL) response to intravenous tryptophan in patients with CFS alone or CFS+FM compared with control subjects. The difference in serotonergic regulation between CFS and FM led us to hypothesize that we would see a significant increase in PRL in the CFS alone

patients but not in those in those with CFS+FM, compared with controls. Finally, we evaluated sex differences in serotonergic-based responses.

Go to: Materials and Methods Subjects

This study was approved by the Institutional Review Board of the New Jersey Medical School. All procedures were carried out with the adequate understanding and written consent of the subjects. Subjects were recruited through the NIAID-funded New Jersey CFS Cooperative Research Center. Women with CFS were referred by their physician or were self-referred in response to media reports, advertisement, or information provided on the Center website. Control subjects were solicited by advertisement or referred by patients. Patients were eligible for study if they fulfilled the 1994 case definition for CFS.2 Therefore, these patients had no known cause for their symptoms based on a physical examination or the results of full blood chemistry examinations, which included tests of thyroid and liver function, electrolytes, urea, full blood count, and erythrocyte sedimentation rate. CFS subjects with comorbid FM were identified using the diagnostic criteria of the American College of Rheumatology.3 Controls were eligible if they reported being in good health, showed no abnormalities on the physical examination, and were not exercising regularly. Subjects were excluded if a structured psychiatric diagnostic interview, the computerized version of the Diagnostic Interview Schedule (DIS),28 showed them positive for psychotic disorders, substance abuse, or eating disorders. In addition, because of the well-known effects of tryptophan in reducing plasma PRL in patients with major depressive disorder (MDD),14 we also excluded 10 subjects (all with CFS and 2 with coexisting FM) with current depression (within the preceding month). Severity of CFS was determined using a method previously described.29 All subjects were medication free for at least 2 weeks prior to testing.

Procedure and measures

Nonmenopausal female subjects were tested during the late follicular phase of their menstrual cycle (714 days after the first day of the last menses). Testing took place in the afternoon after insertion of an intravenous (i.v.) catheter in the antecubital vein. Baseline blood samples were taken 30 and 45 minutes after catheter insertion (t=0 and t=15, respectively). l-

Tryptophan (Ajinomoto U.S.A. Inc., Raleigh, NC) was infused over the following 30 minutes (120mg/kg lean body mass). After completion of the infusion, blood samples were obtained at 15-minute intervals over the next hour. An additional two samples were taken 30 minutes apart. Plasma was collected and stored at 70C.

Plasma PRL was determined using a commercially available radioimmunoassay kit (ICN Pharmaceuticals Inc., Costa Mesa, CA). Interassay and intra-assay coefficients of variation (CV) were 8.2 and 4.1%, respectively. The minimum detectable dose was 0.5ng/mL. Plasma kynurenine and total tryptophan were measured using reverse-phase HPLC with 3-nitro-l-tyrosine as the internal standard, as previously described,30 with some modifications.31 Briefly, 100L of plasma was diluted with 100L of 50M 3-nitro-l-tyrosine, and proteins were precipitated by the addition of 25L of 2M trichloroacetic acid. A reverse-phase 55-mm LiChroCART 55-4 cartridge packed with Purosphere STAR RP18 (3m grain size) (Merk, Darmstadt, Germany) and a C18 precolumn (Merck) were used with a Waters Breeze HPLC system (Milford, MA). The elution buffer contained 15mM acetic acid-sodium acetate (pH 4.0) with 27mM acetonitrile, and the flow rate was 0.9mL/min. The ratios of the integrated areas under the tryptophan and kynurenine peaks to the area under the 3-nitro-l-tyrosine peak were calculated and used to determine the concentrations in the tryptophan and kynurenine peaks. The CV of the internal standard was <5%.

Self-reported measures of energy before and in response to tryptophan infusion were derived from the activation dimension A of the short form of the activation-deactivation checklist (AD ACL).32 The questionnaire was administered before tryptophan infusion (t=0) and at 30-minute intervals after completion of the infusion.

Data analysis

Plasma prolactin, tryptophan, and kynurenine concentrations and AD ACL Energy and Tired scores were each evaluated as a function of time, diagnostic group, and sex. Our primary analyses evaluated differences between the control group and each patient group, CFS only or CFS+FM. These analyses employed mixed model regression (mixed models procedure; SPSS, Inc., Chicago, IL) with random subject and intercept terms. Age and duration of illness were analyzed using a 2-way ANOVA as a function of sex and patient group. Group differences in CFS severity scores were evaluated with the chi-square statistic.

Go to: Results Table 1 shows clinical and baseline physiological characteristics of the sample. The men were generally younger than the women, and whereas there was no difference in the age between groups of women, control men were significantly younger than CFS men (p<0.05). The duration of illness did not differ as a function of sex or CFS group, and there was no difference in CFS severity between the two patient groups or sexes.

Table 1. Clinical Characteristics of Sample Figure 1 shows the PRL response over time for women (Fig. 1A) and men (Fig. 1B). For both men and women, there were increasing plasma PRL levels after infusion with a peak response at about 60 minutes (or 30 minutes postinfusion). Baseline plasma PRL concentrations were similar in the three diagnostic groups. Although the greatest response in the women was seen in the CFS only group, there was no apparent difference in PRL response among diagnostic groups in the men. For women, the mean (SD) maximum PRL increases from baseline were 9.911.2, 18.614.2, and 11.94.8pg/mL for controls, CFS only, and CFS+FM, respectively, whereas comparable values for men were 14.510.9, 13.49.4, and 18.911.8, respectively. Mixed model ANOVA, separated by sex, showed an interaction between diagnosis and time for women [F(16,240)=1.84, p=0.03], but not for men [F(16,104)=0.8, p=0.62]. These data indicate that the magnitude of the PRL response over time varied as a function of diagnostic group, but only among the women.

FIG. 1. Plasma prolactin response to exogenous tryptophan (120mg/kg lean body weight) administered i.v. between 15 and 45 minutes. Among women (A), tryptophan appears to induce a greater plasma prolactin response in the CFS only group, and perhaps in ... To evaluate differences between diagnostic groups within the group of women, we compared PRL changes over time between the control group and each patient group, CFS only and CFS+FM, in separate mixed model

analyses. Results showed differences over time between control and CFS only groups [F(8,184)=2.2, p=0.03] but not between control and CFS+FM groups [F(8,128)=0.6, p=0.76]. Point by point comparisons indicated significantly higher PRL levels in CFS only than control women at all the time points between 75 and 105 minutes postinfusion, inclusive. There were no differences in the baseline levels, and time points after 105 minutes suggested a return to similar baseline levels. Thus, CFS only women, but not men, showed a significantly greater PRL response to tryptophan challenge than did control subjects.

Mean (SD) levels of plasma tryptophan did not differ among study groups at baseline (29.77.4, 30.98.4, and 27.07.7pg/mL for controls, CFS only, and CFS+FM, respectively). Figure 2 shows that after the infusion, plasma concentrations of tryptophan immediately increased approximately 200300 times, followed by a slow decrease over time. Final tryptophan levels were higher than baseline. Although a mixed model ANOVA showed a greater increase in tryptophan over time in men than women [F(8, 330)=4.0, p<0.001], concentrations did not vary as a main effect or interaction with diagnosis. These data confirm that men, who were generally larger, received higher doses of tryptophan.

FIG. 2. Plasma tryptophan concentrations increased significantly over time following tryptophan infusion, moreso in men than in women. However, there were no differences as a function of diagnostic group or interactions of diagnosis with time. Values are given ... Figure 3 shows increasing plasma kynurenine concentrations over time after infusion. The response of men and women was generally similar over time, except between the 60-minute and 75-minute points, where there was a pause in the women's increase. Mixed model ANOVA showed a greater slope over time in men than women [F(8, 330)=4.0, p<0.001]. Plasma kynurenine concentrations did not vary as a function of diagnosis or any interaction. These data confirm the expectation that men, who received higher doses of tryptophan, also produced higher levels of this metabolite.

FIG. 3. Plasma kynurenine concentrations increased significantly in response to tryptophan infusion, moreso in men than in women. However, there were no

differences as a function of diagnostic group or interactions of diagnosis with time. Values are given as ... There was no significant effect of sex on AD ACL Energy scores are shown in Figure 4 as a function of time and group. Repeated measures ANOVA showed an effect of time in both the control (F(4, 56)=11.2, p<0.001) and the CFS only group (F(4, 76)=12.9, p<0.001) but not in the CFS+FM group, which remained at floor levels over time. Post hoc comparisons showed that, relative to baseline, the control group reported less Energy at the 30, 60, and 90 minute assessments and that Energy had recovered to baseline levels at 120 minutes. On the other hand, the CFS only group reported less Energy at all the postinfusion assessments; that is, Energy did not recover to baseline levels by 120 minutes. Sex showed no main or interacting effects with time in these analyses. AD ACL Tired scores showed a similar pattern of response, albeit in the appropriate direction (data not shown). Thus, these analyses suggest that CFS patients may have a different response to tryptophan challenge than do controls. However, the AD ACL did not perform well for the fatigued patients because of marked floor effects prior to tryptophan infusion.

FIG. 4. ADACL energy scores decreased in CFS patients and healthy subjects after tryptophan infusion. Both patient groups had significantly lower Energy scores than controls prior to infusion. Energy scores decreased in response to tryptophan infusion in CFS ... Go to: Discussion Women with CFS alone, but not those with CFS+FM, had a greater PRL response to exogenous tryptophan than did control women. These differences were not found in men with CFS in either group. There were no significant differences in the plasma concentrations of tryptophan or its principal metabolite, kynurenine, between any group either at baseline or in response to tryptophan infusion after groups were stratified by sex. These results suggest differences in central effects of tryptophan among the study groups in producing the enhanced PRL responses to tryptophan seen in CFS only patients.

CFS is predominantly a problem in women's health, occurring more than twice as often in women as in men.33 The reason for this sex predominance in favor of women is unknown, but the data reported here suggest one

mechanism may be via differences in serotonergic function and responsiveness to biological probes. Against this interpretation is the result of an earlier study in men with CFS using fenfluramine as a probe of serotonergic function, which showed an upregulated response compared with controls.15 No differences were found, however, in a mixed gender study in CFS using the same probe.17 Nonetheless, the data reported here using the same experimental protocol to study women and men with CFS do support a biological difference between the sexes that requires further study.

Gender differences as well as the use of pharmacological agents that were not specific to the serotonergic system may explain some of the inconsistent results of prior studies concerning serotonergic tone in CFS. Only one group reduced patient pool heterogeneity by studying only one sex,15,16 and they chose men, substantially less at risk for CFS than women. The probes used in their studies were the 5-HT1A receptor agonist buspirone and the 5-HT-releasing agent d-fenfluramine. Another mixed gender study also found an upregulated PRL response to probe with buspirone,13,16 although buspirone may be having this effect because it also interacts with the dopaminergic system.34 Studies of mixed gender patients with CFS probed with fenfluramine yielded varying results, with one finding significant increases of PRL to the probe14 and two others finding no difference from controls.17,19 Another study in a mixed gender group used the 5-HT2C receptor agonist M-chlorophenylpiperazine (mcpp) and found no evidence for upregulated serotonergic responding.18 However, this probe also has antagonistic properties at 5-HT2A receptors as well as some affinity for 2 adrenoreceptors34 and, thus, is unclear as to its 5-HT-specific effects.

Although gender and nature of the probe may explain these discrepancies in part, another critical variable that has not been studied in any of these reports is the presence of absence of comorbid FM. In fact, the proposed increase in central 5-HT in CFS is virtually opposite that proposed for FM patients. The 5-HT metabolite, 5-HIAA, was at a lower level in the cerebrospinal fluid of patients with FM compared with healthy controls, thus suggestive of decreased central serotonergic tone.35,36 Because plasma PRL levels were higher than in controls in women with CFS alone and similar to levels in controls in women with CFS+FM, we expect that levels might be below those of controls in a future study comparing female patients with FM alone with healthy controls. This would be additional evidence for decreased serotonergic tone in this patient group.

In a more recent study looking at 5-HT1A receptors using positron emission tomography (PET) studies in CFS patients, patients with comorbid FM were

excluded. The binding potential of [11C]WAY-100635 was reduced in CFS patients in a number of brain regions, and the authors suggested this may reflect a downregulation of receptors in response to overall increased serotonergic synaptic transmission.37 Thus, this is additional evidence supporting increased central serotonergic tone specific to CFS alone.

Differences in PRL responses were not due to differences in the metabolism of infused tryptophan to kynurenine or plasma concentrations of total tryptophan achieved in this study. We, therefore, conclude that these effects of tryptophan on PRL release result from differential central effects of tryptophan across patient groups. In previous studies, baseline plasma free tryptophan levels were reported to be significantly greater38 or lower18 among CFS patients than healthy subjects, but total tryptophan concentrations did not differ,18,39 akin to results found in the current study.

We have previously reported significantly lower baseline AD ACL Energy scores and higher Tired scores in CFS patients.40 Exogenous tryptophan (30mg/kg) is known to increase both subjective and objective measures of fatigue,4143 which was also evident in our study with respect to the decrease and increase in AD ACL Energy and Tired scores, respectively, in response to tryptophan infusion. The peak reduction in Energy scores was greater in healthy subjects than in either patient group, and the response in controls, but not patients, waned over time. This difference between patients and controls is most likely driven by a floor effect in the patient groups, each of whom began the study with Energy scores already close to the minimum possible score (minimum and maximum possible scores of 5 and 20, respectively). Developing more sensitive ways to capture subjective and objective fatigue is an important research goal.

As the findings in this study turn on the differences between CFS occurring alone or with comorbid FM, an obvious question concerns the specificity of each diagnosis using clinical criteria dependent on self-reported symptoms. Although CFS patients often have widespread pain, they do not often show the multiple tender points that characterize FM. Obviously, finding biomarkers that differentiate CFS from FM would be an invaluable step forward in adding to the specificity of diagnosis. The data reported here suggest that probing central serotonergic pathways may provide such a biomarker.

In summary, the results of this study are important in that we found only women with CFS alone showed an upregulated PRL response to i.v. tryptophan. This biological difference across the sexes may explain, in part,

the skew toward women in illness prevalence. Importantly, the different results based on the presence or absence of comorbid FM strongly suggest that CFS and FM have different underlying pathophysiological underpinnings. A critical next step will be to extend these studies to include all three patient groups: those with CFS alone, those with CFS+FM, and those with FM alone.

Limitations

We cannot be sure that the differences reported here are specific to the tryptophan infusion or might represent some nonspecific response to a brain-active probe; answering this question would require doing another experiment with a different probe of PRL, such as thyrotropin-releasing hormone (TRH). It remains possible that our results may have occurred from a tryptophan effect in decreasing dopaminergic tone, independent of changes in 5-HT,44 or that differences between the two patient groups in PRL response may have to do with differences in biosynthetic or metabolic products of tryptophan, other than 5-HT, that impact PRL release.45,46 Those questions remain to be answered. The near to the floor baseline measures of Energy and Tired in the CFS groups prevent a clear interpretation of negative findings; it remains possible that more appropriate measures might produce behavioral effects that are consistent with the PRL response. Finally, because CFS is primarily a disease of women, our ability to identify and recruit male patients, especially those with CFS+FM, was restricted; thus, our conclusions were limited by the smaller number of men studied.

Go to: Acknowledgments This work was supported by NIH grant AI-34427 and AI-54478. We acknowledge Beth Israel Medical Center (B.H.N.) and NYU College of Dentistry (M.N.J.) for supporting the preparation of this article.

Go to: Disclosure Statement The authors have no conflicts of interest to report.

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