Tag: Lloyd

A twin study of the etiology of prolonged fatigue and immune activation

Abstract:

Risk factors to prolonged fatigue syndromes (PFS) are controversial. Pre-morbid and/or current psychiatric disturbance, and/or disturbed cell-mediated immunity (CMI), have been proposed as etiologic factors.

Self-report measures of fatigue and psychologic distress and three in vitro measures of CMI were collected from 124 twin pairs. Crosstwin-crosstrait correlations were estimated for the complete monozygotic (MZ; 79 pairs) and dizygotic (DZ; 45 pairs) twin groups. Multivariate genetic and environmental models were fitted to explore the patterns of covariation between etiologic factors. For fatigue, the MZ correlation was more than double the DZ correlation (0.49 versus 0.16) indicating strong genetic control of familial aggregation.

By contrast, for in vitro immune activation measures MZ and DZ correlations were similar (0.49-0.69 versus 0.42-0.53) indicating the etiologic role of shared environments. As small univariate associations were noted between prolonged fatigue and the in vitro immune measures (r = -0.07 to -0.12), multivariate models were fitted. Relevant etiologic factors included: a common genetic factor accounting for 48% of the variance in fatigue which also accounted for 4%, 6% and 8% reductions in immune activation; specific genetic factors for each of the in vitro immune measures; a shared environment factor influencing the three immune activation measures; and, most interestingly, unique environmental influences which increased fatigue but also increased markers of immune activation.

PFS that are associated with in vitro measures of immune activation are most likely to be the consequence of current environmental rather than genetic factors. Such environmental factors could include physical agents such as infection and/or psychologic stress.

 

Source: Hickie IB, Bansal AS, Kirk KM, Lloyd AR, Martin NG. A twin study of the etiology of prolonged fatigue and immune activation. Twin Res. 2001 Apr;4(2):94-102. http://www.ncbi.nlm.nih.gov/pubmed/11665341

 

What is chronic fatigue syndrome? Heterogeneity within an international multicentre study

Abstract:

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.

 

Source: 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. What is chronic fatigue syndrome? Heterogeneity within an international multicentre study. Aust N Z J Psychiatry. 2001 Aug;35(4):520-7. http://www.ncbi.nlm.nih.gov/pubmed/11531735

 

Screening for prolonged fatigue syndromes: validation of the SOFA scale

Abstract:

BACKGROUND: The identification of syndromes characterised by persistent and disabling mental and/or physical fatigue is of renewed interest in psychiatric epidemiology. This report details the development of two specific instruments: the SOFA/CFS for identification of patients with chronic fatigue syndrome (CFS) in specialist clinics and the SOFA/GP for identification of prolonged fatigue syndromes (PFS) in community and primary care settings.

METHODS: Patients with clinical diagnoses of CFS (n = 770) and consecutive attenders at primary care (n = 1593) completed various self-report questionnaires to assess severity of current fatigue-related symptoms and other common somatic and psychological symptoms. Quality receiver operating characteristic curves were used to derive appropriate cut-off scores for each of the instruments. Comparisons with other self-report measures of anxiety, depression and somatic distress are noted. Various multivariate statistical modelling techniques [latent class analysis (LCA), longitudinal LCA] were utilised to define the key features of PFS and describe its longitudinal characteristics.

RESULTS: The SOFA/CFS instrument performs well in specialist samples likely to contain a high proportion of patients with CFS disorders. Cut-off scores of either 1/2 or 2/3 can be used, depending on whether the investigators wish to preferentially emphasise false-negatives or false-positives. Patients from these settings can be thought of as consisting not only of those with a large number of unexplained medical symptoms, but also those with rather specific musculoskeletal and pain syndromes. The SOFA/GP instrument has potential cut-off scores of 1/2 or 2/3, with the latter preferred as it actively excludes all non-PFS cases (sensitivity = 81%, specificity = 100%). Patients with these syndromes in the community represent broader sets of underlying classes, with the emergence of not only musculoskeletal and multisymptomatic disorders, but also persons characterised by significant cognitive subjective impairment. Twelve-month longitudinal analyses of the primary care sample indicated that the underlying class structure was preserved over time. Comparisons with other measures of psychopathology indicated the relative independence of these constructs from conventional notions of anxiety and depression.

CONCLUSIONS: The SOFA/GP instrument (which is considerably modified from the SOFA/CFS in terms of anchor points for severity and chronicity) is preferred for screening in primary care and community settings. Patients with PFS and CFS present a range of psychopathology that differs in its underlying structure, cross-sectionally and longitudinally, from coventional notions of anxiety and depression.

 

Source: Hadzi-Pavlovic D, Hickie IB, Wilson AJ, Davenport TA, Lloyd AR, Wakefield D. Screening for prolonged fatigue syndromes: validation of the SOFA scale. Soc Psychiatry Psychiatr Epidemiol. 2000 Oct;35(10):471-9. http://www.ncbi.nlm.nih.gov/pubmed/11127722

 

A randomized, double-blind placebo-controlled trial of moclobemide in patients with chronic fatigue syndrome

Abstract:

BACKGROUND: Chronic fatigue syndrome is characterized by prolonged and disabling fatigue and a range of neuropsychiatric symptoms including depressed and/or irritable mood. To date, no medical or psychotropic therapies have provided clear symptomatic benefit.

METHOD: Ninety patients with chronic fatigue syndrome, diagnosed with our system that approximates CDC criteria, participated in a randomized, placebo-controlled, double-blind trial of 450 to 600 mg/day of moclobemide, a novel reversible inhibitor of monoamine oxidase-A.

RESULTS: Fifty-one percent (24/47) of patients receiving moclobemide improved compared with 33% (14/43) of patients receiving placebo (odds ratio = 2.16, 95% confidence interval [CI] = 0.9 to 5.1). Drug response was best characterized symptomatically by an increase in the subjective sense of vigor and energy rather than a reduction in depressed mood. The effect of moclobemide on subjective energy was detectable within the first 2 weeks of treatment and increased across the course of the study. The greatest reduction in clinician-rated disability was in patients with concurrent immunologic dysfunction (mean difference in standardized units of improvement = 0.8, 95% CI = 0.03 to 1.6).

CONCLUSION: Moclobemide produces some improvement in key symptoms experienced by patients with chronic fatigue syndrome. This effect is not dependent on the presence of concurrent psychological distress and is likely to be shared with other monoamine oxidase inhibitors.

 

Source: Hickie IB, Wilson AJ, Wright JM, Bennett BK, Wakefield D, Lloyd AR. A randomized, double-blind placebo-controlled trial of moclobemide in patients with chronic fatigue syndrome. J Clin Psychiatry. 2000 Sep;61(9):643-8. http://www.ncbi.nlm.nih.gov/pubmed/11030484

 

Prolonged fatigue, anxiety and depression: exploring relationships in a primary care sample

Abstract:

OBJECTIVE: While prolonged fatigue states are frequently comorbid with other forms of distress, they are now the subject of independent aetiological and treatment research. The objective of this study was to use principal component analysis to clarify the relationships between proposed measures of prolonged fatigue and anxiety and depression in data obtained from patients attending primary care.

METHOD: Self-report measures of prolonged fatigue and psychological distress (anxiety and depression) were administered to consecutive ambulatory care patients attending primary care.

RESULTS: Data from 1593 subjects were obtained. A two-factor principal component solution (varimax rotation) demonstrated a clear separation between fatigue-related items (Cronbach’s alpha = 0.81) as compared with those items describing anxiety and/or depression (Cronbach’s alpha = 0.95). A four-factor solution produced similar results with two factors describing general psychological distress (contrasting anxiety and depression), with two other factors describing the profiles of mental and physical fatigue.

CONCLUSIONS: The results lend weight to the argument that prolonged fatigue states can be measured independently of conventional notions of anxiety and depression in patients attending primary care. Epidemiological, aetiological and treatment research in psychiatry may need to focus greater attention on such prolonged fatigue states.

Comment in: Response to: ‘Prolonged fatigue, anxiety and depression: exploring relationships in a primary care sample‘. [Aust N Z J Psychiatry. 2000]

 

Source: Koschera A, Hickie I, Hadzi-Pavlovic D, Wilson A, Lloyd A. Prolonged fatigue, anxiety and depression: exploring relationships in a primary care sample. Aust N Z J Psychiatry. 1999 Aug;33(4):545-52. http://www.ncbi.nlm.nih.gov/pubmed/10483850

 

The temporal stability and co-morbidity of prolonged fatigue: a longitudinal study in primary care

Abstract:

BACKGROUND: Depression, anxiety and fatigue are among the most common symptoms presented in primary care. Whether such symptoms indicate discrete psychological syndromes or whether they result from a common vulnerability is not clear. This study examined longitudinally the patterns of co-morbidity between prolonged fatigue and other forms of psychological distress in patients attending general practitioners.

METHODS: Adults attending primary care completed questionnaires designed to detect cases of prolonged fatigue and psychological distress at presentation and 12 months later.

RESULTS: Of 652 patients, the prevalence rates of ‘prolonged fatigue’ alone, ‘psychological distress’ alone, ‘prolonged fatigue + psychological distress’ and ‘no disorder’ were 7%, 19%, 15% and 59% respectively at initial assessment. Of those patients with any prolonged fatigue syndrome initially, 58% still reported fatigue 12 months later (representing 13% of the total sample). Most importantly, the risk of developing prolonged fatigue was not increased in patients who initially had psychological distress (OR = 0.95; 95% CI 0.2-3.6), neither was the risk of developing psychological distress increased in patients who initially had prolonged fatigue (OR = 1.4; 95% CI 0.6-3.4).

CONCLUSIONS: This study indicates that prolonged fatigue is a persistent diagnosis over time. The longitudinal patterns of co-morbidity with psychological distress do not support an aetiological model that proposes a common vulnerability factor for these disorders. Psychiatric classification systems may be better served by treating prolonged fatigue and psychological distress as independent disorders.

 

Source: Hickie I, Koschera A, Hadzi-Pavlovic D, Bennett B, Lloyd A. The temporal stability and co-morbidity of prolonged fatigue: a longitudinal study in primary care. Psychol Med. 1999 Jul;29(4):855-61. http://www.ncbi.nlm.nih.gov/pubmed/10473312

 

Chronic fatigue and chronic fatigue syndrome: shifting boundaries and attributions

Abstract:

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.

 

Source: Lloyd AR. Chronic fatigue and chronic fatigue syndrome: shifting boundaries and attributions. Am J Med. 1998 Sep 28;105(3A):7S-10S. http://www.ncbi.nlm.nih.gov/pubmed/9790475

 

Chronic fatigue syndrome: an immunological perspective

Abstract:

OBJECTIVE: The aim of this study is to review research examining an immunological basis for chronic fatigue syndrome (CFS) and to discuss how a disturbance in immunity could produce central nervous system (CNS)-mediated symptoms.

METHOD: Data relevant to the hypothesis that abnormal cytokine release plays a role in the pathogenesis of CFS are reviewed as well as recent evidence relating to potential mechanisms by which immune products may enter the brain and produce a disturbance in CNS processes.

RESULTS: Examinations of cytokine levels in patients with CFS have produced inconclusive results. Recent evidence suggests that abnormal release of cytokines within the CNS may cause neural dysfunction by a variety of complex mechanisms.

CONCLUSION: Neuropsychiatric symptoms in patients with CFS may be more closely related to disordered cytokine production by glial cells within the CNS than to circulating cytokines. This possibility is discussed in the context of unresolved issues in the pathogenesis of CFS.

 

Source: Vollmer-Conna U, Lloyd A, Hickie I, Wakefield D. Chronic fatigue syndrome: an immunological perspective. Aust N Z J Psychiatry. 1998 Aug;32(4):523-7. http://www.ncbi.nlm.nih.gov/pubmed/9711366

 

Cognitive deficits in patients suffering from chronic fatigue syndrome, acute infective illness or depression

Abstract:

BACKGROUND: Patients with chronic fatigue syndrome (CFS) report neuro-psychological symptoms as a characteristic feature. We sought to assess cognitive performance in patients with CFS, and compare cognitive performance and subjective workload experience of these patients with that of two disease comparison groups (non-melancholic depression and acute infection) and healthy controls.

METHOD: A computerized performance battery employed to assess cognitive functioning included tests of continuous attention, response speed, performance accuracy and memory. Severity of mood disturbance and subjective fatigue were assessed by questionnaire.

RESULTS: All patient groups demonstrated increased errors and slower reaction times, and gave higher workload ratings than healthy controls. Patients with CFS and non-melancholic depression had more severe deficits than patients with acute infection. All patient groups reported more severe mood disturbance and fatigue than healthy controls, but patients with CFS and those with acute infection reported less severe mood disturbance than patients with depression.

CONCLUSIONS: As all patients demonstrated similar deficits in attention and response speed, it is possible that common pathophysiological processes are involved. The differences in severity of mood disturbance, however, suggest that the pathophysiological processes in patients with CFS and acute infection are not simply secondary to depressed mood.

 

Source: Vollmer-Conna U, Wakefield D, Lloyd A, Hickie I, Lemon J, Bird KD, Westbrook RF. Cognitive deficits in patients suffering from chronic fatigue syndrome, acute infective illness or depression. Br J Psychiatry. 1997 Oct;171:377-81. http://www.ncbi.nlm.nih.gov/pubmed/9373430

 

Is there a postinfection fatigue syndrome?

Abstract:

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.

 

Source: Hickie I, Lloyd A, Wakefield D, Ricci C. Is there a postinfection fatigue syndrome? Aust Fam Physician. 1996 Dec;25(12):1847-52. http://www.ncbi.nlm.nih.gov/pubmed/9009004