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last revised 11 January 2002CONTENTS
What is chronic fatigue syndrome? Heterogeneity within an international multicentre (2001)
Nefazodone for patients with chronic fatigue syndrome. (Hickie 1999)
Chronic Fatigue and Chronic Fatigue Syndrome: Shifting Boundaries and Attributions (Lloyd, 1998)
Reviving the diagnosis of neurasthenia (1997)
Fatigue in selected primary care settings: sociodemographic and psychiatric correlates. (1996)
Is there a postinfection fatigue syndrome? (1996)
Can the chronic fatigue syndrome be defined by distinct clinical features? (1995)
Chronic fatigue syndrome: current perspectives on evaluation and management. (1995)
Longitudinal study of outcome of chronic fatigue syndrome. (1994)
The treatment of chronic fatigue syndrome: science and speculation. (1994)
The Psychiatric Status of Patients with the Chronic Fatigue Syndrome (1990)
Prevalence of chronic fatigue syndrome in an Australian population (1990)
Journal: Aust N Z J Psychiatry 2001 Aug;35(4):520-527
Authors: Wilson A, Hickie I, Hadzi-Pavlovic D, Wakefield D, Parker G, Straus SE, Dale J, McCluskey D, Hinds G, Brickman A, Goldenberg D, Demitrack M, Blakely T, Wessely S, Sharpe M, Lloyd A.
NLM Citation: PMID: 11531735
OBJECTIVE: We sought to compare the characteristics of patients presenting with chronic fatigue (CF) and related syndromes in eight international centres and to subclassify these subjects based on symptom profiles. The validity of the subclasses was then tested against clinical data.
METHOD: Subjects with a clinical diagnosis of CF completed a 119-item self-report questionnaire to provide clinical symptom data and other information such as illness course and functional impairment. Subclasses were generated using a principal components-like analysis followed by latent profile analysis (LPA).
RESULTS: 744 subjects returned complete data sets (mean age 40.8 years, mean length of illness 7.9 years, female to male ratio 3:1). Overall, the subjects had a high rate of reporting typical CF symptoms (fatigue, neuropsychological dysfunction, sleep disturbance). Using LPA, two subclasses were generated. Class one (68% sample) was characterized by: younger age, lower female to male ratio; shorter episode duration; less premorbid, current and familial psychiatric morbidity; and, less functional disability. Class two subjects (32%) had features more consistent with a somatoform illness. There was substantial variation in subclass prevalences between the study centres (Class two range 6-48%).
CONCLUSIONS: Criteria-based approaches to the diagnosis of CF and related syndromes do not select a homogeneous patient group. While substratification of patients is essential for further aetiological and treatment research, the basis for allocating such subcategories remains controversial.
Nefazodone for patients with chronic fatigue syndrome.
Aust N Z J Psychiatry 1999 Apr;33(2):278-80
Hickie I
St George Hospital and Community Service, Kogarah, New South Wales, Australia.
i.hickie@unsw.edu.au
OBJECTIVE: Patients with chronic fatigue syndrome (CFS) present with a variety of
musculoskeletal, neurocognitive, sleep disturbance and mood symptoms. An open evaluation
of the clinical utility of the novel antidepressant compound, nefazodone [=SERZONE],
was completed.
METHOD: Ten patients with CFS presenting for assessment by a specialist psychiatrist were
treated with nefazodone. Patients treated within this specialist service are also advised
to engage in appropriate behavioural and sleep-wake cycle strategies to improve their
level of functioning.
RESULTS: Of the 10 patients, eight (80%) reported at least some improvement in the key
symptom of fatigue, with four (40%) reporting moderate or marked symptom relief.
Additionally, sleep disturbance and mood were both moderately or markedly improved in
seven (70%) and eight (80%) of the patients, respectively. Five of the patients (50%)
achieved at least a moderate improvement in overall functional outcome and were able to
return to work or their previous level of role function. The mean dose of nefazodone was
370 mg/day (range = 200-800 mg), with a strong preference for nocturnal dosing. Seven of
the patients had previously failed to respond to moclobemide, while seven had previously
failed to respond to conventional antidepressant therapy.
CONCLUSION: Nefazodone appears to be worthy of further systematic investigation in
patients with CFS. Given its effects on sleep, mood and anxiety symptoms, it may have
particular advantages in patients with this disorder.
Publication Types: Clinical trial
PMID: 10336228, UI: 99267270
Chronic Fatigue and Chronic Fatigue Syndrome: Shifting
Boundaries and Attributions
The AMERICAN JOURNAL of MEDICINE. Recent Developments in Chronic Fatigue Syndrome
Am J Med. 1998;105(3A): 7S-10S.
Andrew R. Lloyd, MD
From The Inflammation Research Unit, School of Pathology, University of New South
Wales, Sydney, New South Wales; and the Department of Infectious Diseases, Prince Henry
Hospital, Little Bay, New South Wales.
[Introductory paragraph] The subjective symptom of "fatigue" is one of the most widespread in the general population and is a major source of healthcare utilization. Prolonged fatigue is often associated with neuropsychological and musculoskeletal symptoms that form the basis of several syndromal diagnoses including chronic fatigue syndrome, fibromyalgia, and neurasthenia, and is clearly not simply the result of a lack of force generation from the muscle. Current epidemiologic research in this area relies predominantly on self-report data to document the prevalence and associations of chronic fatigue. Of necessity, this subjective data source gives rise to uncertain diagnostic boundaries and consequent divergent epidemiologic, clinical, and pathophysiologic research findings. This review will highlight the impact of the case definition and ascertainment methods on the varying prevalence estimates of chronic fatigue syndrome and patterns of reported psychological comorbidty. It will also evaluate the evidence for a true postinfective fatigue syndrome.
[text omitted]
CONCLUSIONS
Interpretation and comparison of the results of epidemiologic studies evaluating chronic fatigue and chronic fatigue syndrome should be undertaken only after careful consideration of:
(I) the survey instrument (i.e., the questionnaire) and methodology (e.g., self-report alone versus physician assessment);
(II) the setting from which cases are identified (community surveys versus primary care, or tertiary referral practice); and
(III) the case definition utilized.
Even after these key factors have been taken into consideration it should be recognized that the diagnostic boundaries of chronic fatigue syndrome will necessarily remain uncertain. The syndromes of fibromyalgia and of major depression both feature fatigue. Diagnostic criteria for all 3 conditions overlap substantially. The findings of 2 well-designed, prospective studies have thrown doubt on the link between chronic fatigue syndrome and common viral infections, and yet firmly endorsed the validity of a discrete postinfective fatigue state after infectious mononucleosis. Patients with such postinfective fatigue syndromes represent a subset of those with chronic fatigue syndrome and may provide an invaluable opportunity to define the pathophysiology of this disorder as well as to highlight heterogeneity within the syndrome.
Reviving the diagnosis of neurasthenia
I. HICKIE ; D. HADZI-PAVLOVIC ; C. RICCI
Editorial: Psychological Medicine Volume 27 Issue 5 (1997) pp 989-994
Abstract
´Whether or not it is worthwhile to distinguish between "neurasthenia" and "dysthymic disorders" must depend either on the demonstration that such syndromes have different social covariates, or pursue a different course, or have particular responses to treatment. Until such studies are forthcoming, the distinction seems especially insubstantial.´ (Goldberg & Bridges, 1991)
Epidemiological studies now indicate that fatigue is one of the most common symptoms of ill-health in the community, primary care and other medical settings, and that syndromal diagnoses based on fatigue (including chronic fatigue and neurasthenia) are prevalent and major sources of health care utilization. Such syndromes are characterized by a combination of persistent and disabling fatigue and neuropsychological and neuromuscular symptoms (Lloyd et al. 1990; Angst & Koch, 1991; Sharpe et al. 1991; Fukuda et al. 1994). Essentially, the differences between these syndromes reflect variations in duration criteria rather than symptom constructs. Specifically, the Centers for Disease Control (CDC) defines ´prolonged fatigue´ as a syndrome of at least 1 month's duration, and chronic fatigue (including idiopathic and chronic fatigue syndrome - CFS) as a fatigue syndrome of at least 6 months duration (Fukuda et al. 1994). The ICD-10 classification system (World Health Organization, 1992) now includes a formal diagnosis of neurasthenia (F48.0) based on mental and physical fatigue of at least 3 months duration. Despite the current international and epidemiological interest in these disorders, DSM-IV has simply included them within the ´Undifferentiated Somatoform Disorders - 300.81´ category (American Psychiatric Association, 1994).
Med J Aust 1996 May 20;164(10):585-588
Fatigue in selected primary care settings: sociodemographic
and psychiatric correlates.
Hickie IB, Hooker AW, Hadzi-Pavlovic D, Bennett BK, Wilson AJ, Lloyd AR
School of Psychiatry, University of New South Wales, Sydney, NSW.
OBJECTIVES: To determine the prevalence and sociodemographic and psychiatric correlates
of prolonged fatigue syndromes among patients in primary care.
DESIGN: Prospective questionnaire survey.
PATIENTS AND SETTING: Adults over 18 years attending three general practices in
metropolitan Sydney and one on the Central Coast, north of Sydney.
RESULTS: Of 1593 patients, 25% had prolonged fatigue, while 37% had psychological
disorder. Of the patients with fatigue, 70% had both fatigue and psychological disorder,
while 30% had fatigue only. The factors associated with prolonged fatigue were concurrent
psychological disorder, female gender, lower socioeconomic status and fewer total years of
education. Patients with fatigue were more likely to have a current depressive disorder.
CONCLUSIONS: Prolonged fatigue/neurasthenia syndromes are common in Australian primary
care settings, and are commonly associated with current depressive disorders. Such
syndromes, however, do not fit readily into current international psychiatric
classification systems.
Med J Aust 1996 May 20;164(10):585-588
Aust Fam Physician 1996 Dec;25(12):1847-1852
Is there a postinfection fatigue syndrome?
Hickie I, Lloyd A, Wakefield D, Ricci C
School of Psychiatry, University of New South Wales, Sydney, Australia.
Prolonged fatigue syndromes are common in general practice. Most of these syndromes are secondary to other common medical or psychological disorders. It appears, however, that some specific infectious illnesses are associated with prolonged recovery. Theories as to the mechanisms for such post infection fatigue syndromes include a range of immunological, psychological and neurobiological processes. Current evidence suggests disruption of fundamental central nervous system mechanisms, such as the sleep-wake cycle and the hypothalamic-pituitary-adrenal axis, may underpin the clinical features of this disorder. Treatment should focus on the provision of continuous medical care, physical rehabilitation and adjunctive psychological therapies.
Aust Fam Physician 1996 Dec;25(12):1847-1852
Med J Aust 1995 Sep 18;163(6):314-318
Chronic fatigue syndrome: current perspectives
on evaluation and management.
Hickie IB, Lloyd AR, Wakefield D
University of New South Wales, Sydney.
OBJECTIVE: To describe clinical and laboratory guidelines for assessment and management
of patients presenting with chronic fatigue syndrome (CFS).
DATA SOURCES: Relevant international consensus diagnostic criteria and research literature
on the epidemiology, pathophysiology, concurrent medical and psychological disturbance and
clinical management of CFS.
CONCLUSIONS: Medical and psychiatric morbidity should be carefully assessed and actively
treated, while unnecessary laboratory investigations and extravagant treatment regimens
should be avoided. No single infective agent has been demonstrated as the cause of CFS,
and immunopathological hypotheses remain speculative. The aetiological role of
psychological factors is debated, but they do predict prolonged illness. The rate of
spontaneous recovery appears to be high. Effective clinical management requires a
multidisciplinary approach, with consideration of the medical, psychological and social
factors influencing recovery.
Med J Aust 1995 Sep 18;163(6):314-318
Psychol Med 1995 Sep;25(5):925-935
Can the chronic fatigue syndrome be defined by
distinct clinical features?
Hickie I, Lloyd A, Hadzi-Pavlovic D, Parker G, Bird K, Wakefield D
School of Psychiatry, University of New South Wales, Australia.
To determine whether patients diagnosed as having chronic fatigue syndrome (CFS) constitute a clinically homogeneous class, multivariate statistical analyses were used to derive symptom patterns and potential patient subclasses in 565 patients. The notion that patients currently diagnosed as having CFS constitute a single homogeneous class was rejected. An alternative set of clinical subgroups was derived. The validity of these subgroups was assessed by sociodemographic, psychiatric, immunological and illness behaviour variables. A two-class statistical solution was considered most coherent, with patients from the smaller class (27% of the sample) having clinical characteristics suggestive of somatoform disorders. The larger class (73% of sample) presented a more limited combination of fatigue and neuropsychological symptoms, and only moderate disability but remained heterogeneous clinically. The two patient groups differed with regard to duration of illness, spontaneous recovery, severity of current psychological morbidity, utilization of medical services and CD8 T cell subset counts.The distribution of symptoms among patients was not unimodal, supporting the notion that differences between the proposed subclasses were not due simply to differences in symptom severity. This study demonstrated clinical heterogeneity among patients currently diagnosed as CFS, suggesting aetiological heterogeneity. In the absence of discriminative clinical features, current consensus criteria do not necessarily reduce the heterogeneity of patients recruited to CFS research studies.
Psychol Med 1995 Sep;25(5):925-935
BMJ 1994 Mar 19;308(6931):756-759
Longitudinal study of outcome of chronic fatigue syndrome.
Wilson A, Hickie I, Lloyd A, Hadzi-Pavlovic D, Boughton C, Dwyer J, Wakefield D
Department of Psychiatry, Prince Henry Hospital, Little Bay, NSW, Australia.
OBJECTIVE--To examine the predictors of long term outcome for patients with the chronic
fatigue syndrome.
DESIGN--Cohort study.
SUBJECTS--139 subjects previously enrolled in two treatment trials; 103 (74%) were
reassessed a mean of 3.2 years after start of the trials.
SETTING--University hospital referral centre.
MAIN OUTCOME MEASURES--Age at onset, duration of illness, psychological and immunological
status at initial assessment. Ongoing symptom severity, levels of disability, and
immunological function at follow up.
RESULTS--65 subjects had improved but only six reported no current symptoms. An
alternative medical diagnosis had been made in two and psychiatric illness diagnosed in
20. The assignment of a primary psychiatric diagnosis at follow up and the strength of the
belief that a physical disease process explained all symptoms at entry to the trials both
predicted poor outcome. Age at onset of illness, duration of illness, neuroticism,
premorbid psychiatric diagnoses, and cell mediated immune function did not predict
outcome.
CONCLUSION--Though most patients with the chronic fatigue syndrome improve, a substantial
proportion remain functionally impaired. Psychological factors such as illness attitudes
and coping style seem more important predictors of long term outcome than immunological or
demographic variables.
BMJ 1994 Mar 19;308(6931):756-759
Am J Med 1994 Jun;96(6):544-550
The treatment of chronic fatigue syndrome: science and speculation.
Wilson A, Hickie I, Lloyd A, Wakefield D
Department of Psychiatry, Prince Henry Hospital, Little Bay NSW, Australia.
The chronic fatigue syndrome (CFS) is a heterogeneous disorder characterized by fatigue, neuropsychiatric symptoms, and various other somatic complaints. Treatment studies to date reflect both the diversity of medical disciplines involved in the management of patients with CFS and the multiple pathophysiologic mechanisms proposed. There have been few attempts to study integrated treatment programs, and although several controlled studies have been reported, no treatment has been shown clearly to result in long-term benefit in the majority of patients. Good clinical care integrating medical and psychologic concepts, together with symptomatic management, may prevent significant secondary impairment in the majority of patients. Future treatment studies should examine differential response rates for possible subtypes of the disorder (eg, documented viral onset, concurrent clinical depression), evaluate the extent of any synergistic effects between therapies (ie, medical and psychologic), and employ a wide range of biologic and psychologic parameters as markers of treatment response.
Am J Med 1994 Jun;96(6):544-550
Am J Med 1993 Feb;94(2):197-203
Immunologic and psychologic therapy for patients with
chronic fatigue syndrome: a double-blind, placebo-controlled trial.
Lloyd AR, Hickie I, Brockman A, Hickie C, Wilson A, Dwyer J, Wakefield D
Department of Immunology, Prince Henry Hospital, Sydney, Australia.
PURPOSE: To evaluate the potential benefit of immunologic therapy with dialyzable leukocyte extract and psychologic treatment in the form of cognitive-behavioral therapy (CBT) in patients with chronic fatigue syndrome (CFS).
["Patients and Methods" omitted]
CONCLUSIONS: In this study, patients with CFS did not demonstrate a specific response to immunologic and/or psychologic therapy. The improvement recorded in the group as a whole may reflect both nonspecific treatment effects and a propensity to remission in the natural history of this disorder.
Am J Med 1993 Feb;94(2):197-203
Immunological and psychological dysfunction in
patients receiving immunotherapy for chronic fatigue syndrome.
Aust N Z J Psychiatry 1992 Jun;26(2):249-56
Hickie I, Lloyd A, Wakefield D Mood Disorders Unit, Prince Henry Hospital, Little Bay, NSW.
Associations between immunological and psychological dysfunction in 33 patients with Chronic Fatigue Syndrome (CFS) were examined before and in response to treatment in a double blind, placebo-controlled trial of high dose intravenous immunoglobulin. Only those patients who received active immunotherapy demonstrated a consistent pattern of correlations between improvement in depressive symptoms and markers of cell-mediated immunity (CMI). This finding lends some support to the hypothesis that depressive symptoms in patients with CFS occur secondary to, or share a common pathophysiology with, immunological dysfunction. This pattern and the lack of strong associations between depression and immunological disturbance prior to treatment are less supportive of the view that CFS is primarily a form of depressive disorder or that immunological dysfunction in patients with CFS is secondary to concurrent depression.
Publication Types: Clinical trial Controlled clinical trial
PMID: 1642616, UI: 92352425
The Psychiatric Status of Patients with the Chronic
Fatigue Syndrome
Ian Hickie, Andrew Lloyd, Denis Wakefield and Gordon Parker
British Journal of Psychiatry (1990), 156, 534 - 540
The prevalence of psychiatric disorder in 48 patients with chronic fatigue syndrome (CFS) was determined. Twenty-two had had a major depressive (non-endogenous) episode during the course of their illness, while seven had a current major (non-endogenous) depression. The pre-morbid prevalence of major depression (12.5%) and of total psychiatric disorder (24.5%) was no higher than general community estimates. The pattern of psychiatric symptoms in the CFS patients was significantly different to that of 48 patients with non-endogenous depression, but was comparable with that observed in other medical disorders. Patients with CFS were not excessively hypochrondriacal. We conclude that psychological disturbance is likely to be a consequence of, rather than an antecedent risk factor to the syndrome.
Med J Aust Vol 153 November 5, 1990
Prevalence of chronic fatigue syndrome in an Australian
population
Andrew R Lloyd, Ian Hickie, Clement R Boughton, Owen Spencer and Denis Wakefield
Departments of Immunology and Infectious Diseases, Division of Medicine and the Mood Disorders Unit, Division of Psychiatry, The Prince Henry Hospital, Little Bay, NSW 2036. Andrew R Lloyd, MB BS, FRACP, NHMRC Postgraduate Scholar, Department of Infectious Diseases. Ian Hickie, MB BS, FRANZCP. Staff Specialist in Psychiatry, Mood Disorders Unit. Clement R Boughton, MD, FRACP, FRCP, DTM&H, Associate Professor, Department of infectious Diseases. Denis Wakefield, MD, FRACP, FRCPA, Associate Professor, Immunopathology Department. North Coast Health Region, Department of Health, Lismore, HSW 2480. Owen Spencer, MB BS, MPH, Director of Clinical Services; currently Regional Director, New England Health Region. Reprints: Associate Professor Denis Wakefield.
ABSTRACT An epidemiological study was undertaken to provide the first reported estimate of the point prevalence of chronic fatigue syndrome in an Australian community. After a pilot study in a separate location, the population of the Richmond Valley, New South Wales, was sampled using a structured case-finding technique, which included notification from local medical practitioners, the use of a screening questionnaire and standardised interviews conducted by a physician and psychiatrist. In addition, investigations were performed to exclude alternative diagnoses and to assess cell-mediated immunity. Forty-two patients with chronic fatigue syndrome, with a female:male ratio of 1.3:1.0, were detected in a population of 114 000. The mean age at onset of symptoms was 28.6 years (SD, 12.3 years), and the median duration of symptoms from onset to sampling date was 30 months. The social status of the patients was distributed in accordance with that of the remainder of the population sampled, with no bias towards the middle or upper social classes. The disorder was causing considerable incapacity, with 43% of patients unable to attend school or work. The conservative estimate from this study suggests a prevalence on June 30 1988 of 37.1 cases per 100 000 (95% confidence interval [Cl], 26.8-50.2). Chronic fatigue syndrome is an important disorder in this Australian community that affects young individuals from all social classes and causes considerable ill health and disability.
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last revised 11 January 2002