Major Depressive Disorder in Chronic Fatigue Syndrome: A CDC Surveillance Study
December 28, 2005
Source: Journal of Chronic Fatigue Syndrome, Vol. 12(3) 2004
Authors: Eleanor K. Axe, M.D., Ph.D., Paul Satz, Ph.D., Natalia L. Rasgon, M.D., Ph.D., Fawzy I. Fawzy, M.D.
Editor’s note: The following is not the complete study text, but rather the abstract, and the introduction to the study followed by the authors’ discussion of the study results.
Controversy continues to exist as to whether Chronic Fatigue Syndrome (CFS) is a psychological/psychiatric disorder. To further understand this condition, the Centers for Disease Control (CDC) conducted a Surveillance study. The CDC partitioned 565 subjects with fatiguing illnesses into four diagnostic groups, one of which met the 1988 CDC criteria for CFS. The non-CFS groups had either insufficient severity (idiopathic), medical exclusions or prior psychiatric disorders.
Objectives: The present study reports on the psychiatric features in that study, estimates the time of onset of Major Depressive Disorder (MDD) and looks for possible relationships between 1988 CDC criteria for Chronic Fatigue Syndrome and psychiatric disorders.
Methods: The study design is cross-sectional. The Diagnostic Interview Schedule (DIS) assessed for four Axis I psychiatric disorders. Time of onset of MDD was estimated from the DIS and validated by an examination of the medical records. Odds ratios and confidence intervals were calculated as tests of association between 1988 CDC criteria and psychiatric disorders.
Results: Subjects classified as CFS and non-CFS had similar rates of psychiatric disorders. A minority of subjects had preexisting MDD. Three 1988 CDC criteria were associated with current MDD whilst no criteria were associated with prior MDD.
Conclusions: CFS subjects did not demonstrate any unique patterns of psychiatric disorders. MDD may not be an important predisposing factor for CFS or other fatiguing illnesses. Some 1988 CDC criteria may be preferentially endorsed by subjects with current MDD.
The literature on Chronic Fatigue Syndrome (CFS) is polarized into those who view the disorder(s) within a psychological/psychiatric context, and those who view it within a neurological context. The former and traditional view often called neurasthenia notes the predominance of psychiatric disorders in CFS (primarily major depression) as a culturally sanctioned form of illness behavior. The later of more recent view notes that many of the 1988 CDC criteria for CFS including prolonged debilitating fatigue worsened after physical exertion, painful lymph nodes, sore throat and sudden onset, are less commonly observed in Major Depressive Disorder (MDD) and point to a different underlying etiology.
The CDC now places CFS at the top priority of new and reemerging infectious diseases(1). Markers of persistent infection (2) and acquired immune dysregulation (3-5) have been reported in CFS. While to date CFS has no widely acceptable biological markers, it is clearly a disabling condition with features that suggest neurobehavioral and multisystem involvement.
A.R. Damasio (6) suggested that Descartes’ theory that the mind and body are separate, has had an adverse influence on the Western approach to illness. C. Ray (7) stated that disorders with a psychological component may not necessarily primarily have a psychological basis. The issue is pertinent because the literature suggests that MDD is a predominant psychiatric disorder accompanying CFS. Possible interpretations are that (1) MDD results in CFS, (2) MDD-like symptoms follow CFS, (3) MDD and CFS share common etiological factors, and (4) CFS is a heterogeneous condition where only some phenotypes have MDD. Van Hoof et al (8) proposed that MDD-like symptoms following CFS represent not atypical depression but sickness-response behaviors.
If a temporal relationship between MDD and CFS were to be established there might be a better understanding of CFS. To investigate this issue, we reviewed studies that utilized an accepted CFS case definition, administered a standardized instrument to diagnose MDD (9) and estimated a temporal relationship between CFS and MDD.
Four reviewed studies were selected. The proportions of CFS subjects with a concurrent onset of MDD (acquired) were: 45.3% (10), 45.8% (11), 30% (12) and 20% (13). The proportions where MDD began prior to CFS (preexisting) were: 16.4%. 12.5%, 15%, and 0%, respectively. Comparatively low reported levels of preexisting MDD suggest the MDD may not be a necessary risk factor for CFS. However, it is difficult to draw firm conclusions regarding temporality because of the paucity of studies, possibilities of selection bias, small sample sizes, and the retrospective nature of the inquiry. There is also a problem of heterogeneity of the subjects.
When four published CFS case definitions were compared (14-17), they were shown to have an overlapping of caseness (18). According to De Becker, McGregor, and De Meirleir (19), the case definition could be improved by modifying its criteria. They suggested that the symptom “arthralgia” be deleted. However, Axe (20) found correlations between arthralgia and neurocognitive difficulty. For the present study, we used the 1988 CDC criteria because the CDC could not guarantee a reliable reclassification of subjects for the 1994 CDC criteria.
The present study utilizes data from the CDC’s Chronic Fatigue Syndrome Surveillance System (21), one of the largest and richest epidemiologic investigative studies pertaining to this subject. It will ascertain if CFS subjects have unique psychiatric features, judge whether MDD is a risk factor for CFS subjects and investigate whether 1988 CDC criteria are associated with psychiatric disturbances.
While high rates of psychiatric disorders were seen in the present study, the effect was largely seen for one disorder, namely MDD. This finding is consistent with the literature where for the most part MDD was the predominant disorder. The test instrument used in the present study to assess psychiatric disorders was the DIS, while the reviewed studies used the Structured Clinical Interview for DSM-III-R (SCID). Despite the different test instruments, rates of MDD in the present study were comparable to two reviewed studies (10,11). Lower rates found in the other two studies may be explained by a possibility of selection bias. Krupp (12) excluded subjects with high scores on the Center for Epidemiological Studies Depression Scale (23) and Pepper (13) lost subjects referred to psychiatry. Taylor and Jason (24) favor the SCID, however further work is needed to determine which may be the better test instrument.
In this study, 46.7% were not currently depressed, and 38.9% were never depressed. The fact that MDD had resolved in the remaining 7.8% also suggests that MDD is an unlikely risk factor for the fatiguing illnesses. Hickie et al (25) reported that the prevalence of premorbid psychiatric disorders in CFS was similar to that of a normal population estimate (ECA) which further dampens prevailing view on the role of prior MDD in these disorders. A low proportion of Somatization Disorder (4.9%) brings to mind that the traditional neurasthenia hypothesis may also not be a predominant cofactor in the fatiguing illnesses.
In an effort to further delineate psychiatric disorders, we investigated whether subjects with psychiatric disorders reported more 1988 criteria. A dose-response effect was not seen in subjects with current MDD and Somatization. However, when using the same data (2) and stratifying subjects by age, education, and gender, these differences ceased to exist.
We investigated whether psychiatric disorders were associated with individual 1988 CDC criteria. There was no association for prior psychiatric disorders whatsoever. Subjects with only current MDD preferentially endorsed two 1988 CDC criteria: sleep disturbance and cognitive complaints (neurobehavioral). A body of research confirms associations of MDD with sleep disturbance and polysomnographic abnormalities (27). With respect to cognitive complaints, the present data set assessed for forgetfulness, confusion, difficulty thinking, and difficulty with concentration. Wearden and Appleby (28) noted that reports of general cognitive functioning were associated with mood in CFS patients. Noting a disparity between cognitive complaints and test performance, they suggested that cognitive complaints be distinguished from cognitive difficulty. The literature supports our findings that sleep disorders and cognitive complaints correlate with psychiatric disorders.
The frequency of psychiatric disorders in the present study was similar in CFS and non-CFS subjects. These results raise concerns regarding the 1988 CDC criteria and suggest that a priori subtyping of persons be abandoned in favor of empirically-driven phenotypes that partition the apparent heterogeneity more testable and meaningful subgroups using variables external to the subtype classification for validation.
A second candidate variable in this context would involve neurocognitive functioning. A comprehensive study of CFS patients (29) found associations between poor neurocognitive functioning and immune system abnormalities which persisted after controlling for depression. Results from a recent unpublished dissertation study (20) found a cognitive disorder phenotype with a pattern of psychomotor speed and executive impairment similar to that seen in immunocompromised HIV patients (30). The dissociation between depression and cognitive performance (but not cognitive complaints) has been reported in other CFS studies and in HIV studies (25,30,32,33).
The information gained in this study may be useful to future researchers to reduce heterogeneity. For example, the MDD subtypes represent a classification system that might provide insights into etiology and treatment. Two clinical phenotypes offer a potentially useful approach in the search for a neurobiological mechanism or substrate, namely: those patients who never had major depression, and those with preexisting depression. The former is hypothesized to represent a more homogenous neurobiological type, unconfounded by psychiatric factors. The latter might be a predominantly psychiatric or neurasthenic group consistent with the traditional views.
But what about those with an onset of depression acquired after the fatiguing illness, some of whose members have been shown to have cognitive impairment? It would be imprudent to dismiss a separate underlying neurobiological substrate in this group, despite the presence of current major depression. In this case, treatment strategies would have to consider both neurological and psychiatric disorders. Because these hypotheses go beyond the scope of the present data, they should be viewed as speculative at this time.
This study has some limitations. It originated in primary case settings (7) which are subject to more referral bias than studies that describe CFS in the community. It lacked normal internal control subjects. It also used prevalence measures which are not as useful as incidence measures (34). More recent CDC studies incorporate incidence measures (35). The CDC did not make available raw DIS scores or the algorithm used to make psychiatric diagnoses. The present study could not analyze the individual responses in the DIS used to establish the psychiatric diagnoses.
This study benefited from having a richness of data and a large sample size, although in males the Diagnostic Groups were sometimes rather small. The first classification used compared subjects according to the Diagnostic Groups. The subjects were later stratified differently to characterize the times of onset of MDD and test for quantitative and qualitative associations between MDD and 1988 CDC criteria. These stratifications may be useful to guide future studies to disentangle some of the ambiguity associated with current views of CFS.
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