| | Psychiatric Comorbidity and Other Psychological Factors in Patients with “Chronic Lyme Disease”Abstract BackgroundThere is no evidence of current or previous Borrelia burgdorferi infection in most patients evaluated at university-based Lyme disease referral centers. Instead, psychological factors likely exacerbate the persistent diffuse symptoms or “Chronic Multisymptom Illness” (CMI) incorrectly ascribed to an ongoing chronic infection with B. burgdorferi. The objective of this study was to assess the medical and psychiatric status of such patients and compare these findings to those from patients without CMI. MethodsThere were 240 consecutive patients who underwent medical evaluation and were screened for clinical disorders (eg, depression and anxiety) with diagnoses confirmed by structured clinical interviews at an academic Lyme disease referral center in New Jersey. Personality disorders, catastrophizing, and negative and positive affect also were evaluated, and all factors were compared between groups and with functional outcomes. ResultsOf our sample, 60.4% had symptoms that could not be explained by current Lyme disease or another medical condition other than CMI. After adjusting for age and sex, clinical disorders were more common in CMI than in the comparison group (P <.001, odds ratio 3.54, 95% confidence interval, 1.97-6.55), but personality disorders were not significantly more common. CMI patients had higher negative affect, lower positive affect, and a greater tendency to catastrophize pain (P <.001) than did the comparison group. Except for personality disorders, all psychological factors were related to worse functioning. Our explanatory model based on these factors was confirmed. ConclusionsPsychiatric comorbidity and other psychological factors are prominent in the presentation and outcome of some patients who inaccurately ascribe longstanding symptoms to “chronic Lyme disease.” Lyme disease is a multisystem inflammatory disorder due to a symptomatic infection with the tick-borne organism Borrelia burgdorferi.1 Clinical features, including erythema migrans rash, musculoskeletal pain, and joint inflammation, typically resolve with conventional antibiotic treatment.2 Rarely do patients treated with adequate antibiotic therapy continue to manifest objective evidence of ongoing infection. Yet, in studies of post-therapy complaints, 4%-40% of adult patients reported chronic physical, cognitive, or mood symptoms attributed to Lyme disease.3, 4, 5, 6, 7, 8 Clinical Significance•Misdiagnosis of Lyme disease was common, often resulting in repeated and unnecessary antibiotic treatment(s) for patients with well-defined medical conditions other than Lyme disease, as well as those with chronic diffuse symptoms or “Chronic Multisymptom Illness” (CMI). •Psychiatric comorbidity, especially depression and anxiety, and other psychological factors distinguished CMI patients from those with medical conditions other than CMI. •Psychiatric comorbidity and other psychological factors were associated with functional outcomes. Post Lyme Disease Syndrome refers to symptoms that continue 6 months after initial diagnosis and treatment.2 Despite evidence from animal studies that viable B. burgdorferi can persist after antibiotic therapy,9 there is no evidence of ongoing B. burgdorferi infection in humans.10, 11 Nonetheless, these patients are diagnosed as having “chronic Lyme disease”—assumed to be a persistent, perhaps incurable, infection.12 Extended courses of antibiotic therapy are often prescribed for their “infection,”2, 13, 14, 15, 16 even though double-blind, placebo-controlled studies have shown that such therapies provide no benefit.17 Frequently, symptoms are best explained by fibromyalgia4, 14, 16, 18, 19 and respond to treatment for this noninfectious disorder. A second group of patients accounts for up to three quarters of patients seen in university-based Lyme disease referral centers.14, 19, 20 These patients report multiple unexplained symptoms ascribed to “chronic Lyme disease” but do not have an illness or objective evidence explicitly suggesting Lyme disease. Some patients are self-diagnosed, while others are misdiagnosed by physicians using nonvalidated laboratory tests, applying alternative criteria in the interpretation of validated laboratory tests, or eschewing laboratory tests entirely, alleging fallibility and inaccuracy.14, 18, 21 Many of these patients also inappropriately receive long-term or repeated antibiotic therapy.2, 14, 15, 16, 19 Similar to Post Lyme Disease Syndrome patients, these patients experience numerous nonspecific complaints, for example, joint and muscle pain, fatigue, headache, and cognitive impairment, that are often complicated by depression,16, 19 psychological stress,19 and the presence of other stress-related syndromes, especially fibromyalgia.14, 16, 19, 20 Conditions including, but not limited to, fibromyalgia, chronic fatigue syndrome, and Gulf War syndrome can be considered collectively as Chronic Multisymptom Illness.22 The case definition for Chronic Multisymptom Illness has included having at least one or more chronic symptoms from at least 2 of 3 categories of symptoms including musculoskeletal, fatigue, and mood cognition.22 Previous findings and our own clinical observations suggest that the complaints of some patients presenting to Lyme disease referral centers might have explanations rooted in psychological distress.16, 19, 23 Not only does mood disturbance appear to be common among these patients,19 but one study found a relationship between prior psychological trauma or treatment with psychotropic medication and poor outcome in Lyme disease patients.24 However, psychological factors have not been adequately studied in the full range of patients presenting to Lyme disease centers. Of importance are both broad categories of psychiatric conditions: clinical disorders (eg, depression, anxiety, somatization) and personality disorders (ie, inflexible, maladaptive, and enduring personality traits causing distress or functional impairment).25 In addition to psychiatric disorders, maladaptive emotional and cognitive/coping factors associated with poor outcomes should be evaluated. The objective of this cross-sectional study was to evaluate a large patient cohort representative of those seen in our Lyme disease referral center over the last 20 years. We assessed clinical and personality disorders, as well as a potential role for negative and positive affect (emotional state) and catastrophizing (maladaptive coping). Psychological factors were then compared between groups (those with and those without Chronic Multisymptom Illness) and with functional outcomes. An explanatory model for group inclusion consisting of clinical disorders, personality disorders, negative and positive affect, and catastrophizing was tested. Methods  Participants We recruited 240 patients from the Lyme Disease Center at the University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School (UMDNJ-RWJMS). Participants were predominantly residents of New Jersey, New York, Connecticut, and Pennsylvania—areas endemic for Lyme disease. Most were referred by physicians in their communities, while others were self-referred. The Institutional Review Board of UMDNJ-RWJMS approved this study. Procedures All English-speaking patients aged 18-70 years presenting to the Lyme Disease Center for an initial visit were invited to participate. Enrollment and tracking took place from September 2002 through March 2007. Patients arrived 1 hour before their appointment and completed consent forms and questionnaires in a private room. Structured clinical interviews were conducted when indicated by screening. Fewer than 17% (49 patients) declined to participate or did not complete at least 75% of the questionnaires. Participants were paid $10. LHS conducted a standard medical evaluation for Lyme disease including a diagnostic interview, physical examination, and chart/records review. Special reference was given to the results and location of prior laboratory testing. Two-tiered serological testing (enzyme-linked immunosorbent assay and Western Blot) was ordered when current but previously undiagnosed Lyme disease was suspected. For patients diagnosed as having untreated Lyme disease, antibiotic therapy was offered. These patients were reexamined at regular intervals and contacted by telephone 6 months post-treatment to evaluate the persistence of Lyme disease-related symptoms. Explanations other than Lyme disease were sought for all patients' complaints, for example, osteoarthritis, systemic lupus erythematosus, fibromyalgia, Parkinson disease, amyotrophic lateral sclerosis, antiphospholipid antibody syndrome (all diagnoses made in the past in patients referred for evaluation of Lyme disease),14 and appropriate treatments and referrals were recommended. When diagnosis was unclear, patients were tracked and reviewed by LHS upon receiving test or referral results. Blind to questionnaire findings, LHS assigned patients to 1 of 4 groups described below. Chronic Multisymptom Illness Group 2: Fibromyalgia These patients did not meet CDC criteria for Lyme disease at the onset of their symptoms;26 nonetheless, symptoms were attributed to Lyme disease. These patients met the American College of Rheumatology criteria for fibromyalgia28 and no other medical condition. Chronic Multisymptom Illness Group 3: Medically Unexplained Symptoms These patients did not meet CDC criteria for Lyme disease at the onset of their symptoms26 and their multiple symptoms could not be accounted for by a medical condition. There was little or no evidence of fibromyalgia at evaluation. Comparison Group Patients without Chronic Multisymptom Illness included those diagnosed by LHS as having previously untreated Lyme disease based on CDC criteria.26 These patients were offered antibiotic therapy and contacted 6 months post-treatment for a telephone interview. Patients denying symptoms related to Lyme disease were considered recovered and assigned to the comparison group. Others without Chronic Multisymptom Illness had well-defined medical conditions, for example, osteoarthritis, or were deemed “healthy,” meaning that they had no chronic symptoms but were concerned about possible exposure, for example, found tick on clothing. Assessment Measures Most studies assessing psychiatric comorbidity typically consider “depression” or “anxiety” using questionnaires that rarely result in a concrete diagnosis. Herein, participants were evaluated rigorously for the presence of clinical disorders like Major Depressive Disorder, Generalized Anxiety Disorder, and Post-traumatic Stress Disorder. The PRIME MD Patient Health Questionnaire was used to screen patients for the presence of clinical disorders, which, for the purposes of this study, included diagnoses falling under the broader categories of mood, anxiety, somatoform, eating, and substance use disorders.29 Next, to explore positive screening results, corresponding modules from the Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders30 were used to identify definitive diagnoses. Psychiatric comorbidity also includes personality disorders; however, this other broad category is rarely explored. Personality disorders can co-occur with clinical disorders, but by definition represent an enduring pattern of maladaptive personality traits that are relatively stable over time and apparent in the absence of a clinical disorder such as Major Depressive Disorder.25 The most extensively used written assessment instrument for personality disorders, the Millon Clinical Multiaxial Inventory-III,31, 32 was used to evaluate personality disorders. The single highest scale score was considered the best indicator of personality style. A cutoff score of 90 was used instead of the traditional cutoff score of 85 to reduce false positives.33 The Coping Strategies Questionnaire's catastrophizing subscale34 assessed catastrophizing, a dysfunctional cognitive process associated with poor medical outcomes in rheumatologic populations.35 Catastrophizing is characterized by pessimistic beliefs where one anticipates the worst-case scenario. The catastrophizing subscale has good construct validity.36 The Positive and Negative Affect Scale evaluated emotional characteristics.37 This reliable and valid self-report questionnaire consists of 2 mood scales with 10 items each for the assessment of positive affect (eg, inspired, enthusiastic) and negative affect (eg, nervous, scared).37 Lastly, because fibromyalgia is common in this patient population,14, 18, 20 level of functioning was determined by the global score from the Fibromyalgia Impact Questionnaire (FIQ). The FIQ is a 19-item self-report instrument with a mean of 50 and SD of 10, where higher scores indicate worse functioning.38 A version of the FIQ modified for Lyme disease patients was used.39 Statistical Analyses In most cases, the comparison group was compared with the larger Chronic Multisymptom Illness group consisting of all 3 conditions. Linear regression was used to analyze continuous response variables (positive affect, negative affect, catastrophizing, and functioning), while logistic regression was used for binary responses (group membership, presence of clinical and personality disorders) and Poisson regression was used for the response of symptom number. Age and sex were used as covariates in all analyses, with the consequence that estimated differences and odds ratios are adjusted for age and sex. For secondary analyses, Tukey's pairwise comparison method was used to compare subgroups. Variables in the predictive model were determined a priori, so no model selection was performed. Somers' Dxy rank correlation40 was used to summarize the predictive capability of the model; 0.0 corresponds to no better than random predictions within discordant pairs, while 1.00 corresponds to perfect predictions. P-values and confidence intervals are not adjusted for multiple testing. The R statistical environment was used for analysis,41 while the SPSS program (SPSS Inc., Chicago, Ill) was used for recording data and generating tables. Results Symptoms, Physical Examination, and Inappropriate Antibiotic Treatment In a secondary analysis, the 2 subgroups of the comparison group did not differ significantly (Tukey's pairwise comparisons) on any of the primary outcomes. Similarly, the 3 Chronic Multisymptom Illness subgroups did not differ significantly among themselves on any of the primary outcomes. Patients in the Chronic Multisymptom Illness groups reported 47% more physical symptoms than did the comparison group (P <.001; 95% confidence interval [CI], 33%-62%) with Chronic Multisymptom Illness patients commonly reporting pain (97.2%), fatigue (91.7%), poor concentration (74.5%), and sleep disturbance (75.9%). Patients in the Chronic Multisymptom Illness group had few observable clinical signs like joint inflammation (2.1%) that could be misinterpreted as indicative of Lyme disease. In Chronic Multisymptom Illness patients, equivocal test results, unreliable tests (eg, Lyme urine antigen test), or unproven laboratories appeared to contribute heavily to previous misdiagnosis. Although 169 (70.4%) patients at no time met criteria for Lyme disease, 114 (67.5%) of them had received at least one course of oral or intravenous antibiotics. Thirty-three (28.9%) of the 114 patients received multiple courses of oral antibiotics, while intravenous antibiotics were provided for 22 patients, with 12 receiving repeated intravenous antibiotic treatment often over a period of months or years. Nineteen (35.8%) of the 53 comparison group patients with medical conditions (not Lyme disease) received antibiotic treatment, with 9 receiving multiple courses of antimicrobials. Associated Cognitive, Affective and Functional Outcomes Chronic Multisymptom Illness patients were more likely than comparison group patients to have lower levels of positive affect (P <.001, mean difference −4.3, 95% CI, −6.4 to −2.2), higher levels of negative affect (P <.001, mean difference +3.7, 95% CI, 1.7-5.7) and a greater tendency to catastrophize pain (P <.001, difference of 5.8, 95% CI, 3.0-7.8). The Chronic Multisymptom Illness group had worse functioning scores than did the comparison group (P <.001; increase of 15.1, 95% CI, 10.3-19.9) and these scores were related to catastrophizing (r =.522, P <.001), negative affect (r=.483, P <.001) and positive affect (r=−.342, P <.001). Lastly, clinical disorders were predictive of worse functioning scores for all patients (P <.001, difference of 21.6, 95% CI, 17.1-26.1). Explanatory Model The hypothesized prediction model consisting of age, sex, clinical disorders, personality disorders, catastrophizing, positive affect, and negative affect adequately accounted for group inclusion (Table 5; P <.001 compared with a base model of age and sex only), with a Somers' Dxy rank correlation of .53. Catastrophizing, positive affect, and personality disorders all significantly contributed to the model after accounting for other effects, with odds ratios for the Chronic Multisymptom Illness groups of 2.09, 0.64, and 2.35, respectively, for an increase of 10 on the catastrophizing scale, an increase of 10 on the positive affect scale, or the presence of a personality disorder. | | |  | Factor | P Value | Odds Ratio | 95% CI for OR | |
|---|
| Age | .68 | 0.95 | (0.76-1.20) | | | Sex | .67 | 0.86 | (0.44-1.69) | | | Catastrophizing | .005 | 2.09 | (1.25-3.47) | | | Negative Affect | .71 | 1.10 | (0.67-1.82) | | | Positive Affect | .04 | 0.64 | (0.41-0.98) | | | Clinical Disorders | .08 | 1.96 | (0.93-4.12) | | | Personality Disorders | .02 | 2.35 | (1.15-4.82) | | | | |
It is worth noting that although the clinical disorder rate differed significantly between groups (Chronic Multisymptom Illness and comparison) while the personality disorder rate did not, as discussed above, in the predictive model the opposite was true with regard to significance. As the tests in the predictive model can be thought of as adjusting for the other terms, these results reflect the relations among the terms in the predictive model and suggest the importance of considering several measures simultaneously. Discussion Our data supported previous observations that the chronic symptoms of most patients presenting to academic Lyme disease referral centers cannot be attributed to ongoing infection with B. burgdoferi.14, 19, 20 While some of our patients had another medical condition that explained the complaints attributed to Lyme disease, the physical, cognitive, and emotional symptoms of most patients were more consistent with Chronic Multisymptom Illness or psychiatric disorders. Almost 49% of patients in our Chronic Multisymptom Illness group had clinical disorders like Major Depressive Disorder or Generalized Anxiety Disorder, in contrast to the comparison group with a rate of 21.1%, which is closer to the rate observed in the general population, 26.2%.42 In addition, psychological factors associated with poor medical outcomes including catastrophizing, high negative affect, and low positive affect were more pronounced in Chronic Multisymptom Illness than in the comparison group. A model based on psychiatric co-morbidity and these 3 psychological factors predicted the likelihood that a patient would be included in a Chronic Multisymptom Illness group. Moreover, the presence of clinical disorders, catastrophizing, high negative affect, and low positive affect were highly related to poor functioning. We did not find personality disorders to be predictive of Chronic Multisymptom Illness group inclusion, although 2 of 3 Chronic Multisymptom Illness groups had elevated rates (Post Lyme Disease Syndrome=29.0% and fibromyalgia=38.9%) not seen in the comparison group (21.1%) or in the general population (∼9%).43 Of interest, the presence of personality disorders did contribute significantly to our predictive model, which emphasizes the importance of considering the relationships among several variables at once. However, our instrument is known to produce a high rate of false positives and, despite our efforts to control for this, false positives could have been a problem herein. Others have found lower rates of personality disorders in fibromyalgia (8.7%).44 Despite these caveats, Lamberg noted that personality disorder is frequently present in some of our most “difficult” medical patients whether their symptoms are medically explained or not.45 Conversely, half of our Chronic Multisymptom Illness patients did not meet criteria for psychiatric co-morbidity, which is consistent with other reports describing subgroups of psychologically healthy fibromyalgia patients who in one study reported lower levels of pain despite increased pain sensitivity.46 Chronic Multisymptom Illness patients had 47% more symptoms than the comparison patients, and medicalizing these symptoms has adverse consequences for Chronic Multisymptom Illness patients. When attributing symptoms to an infectious disease, unnecessary antibiotic treatment is often given. Almost 68% of our patients with no evidence of Lyme disease received antibiotic treatment; 29% of them received multiple antimicrobials for months or even years. Baker recently argued that despite convincing results otherwise, some maintain that “chronic Lyme disease” is the result of a persistent infection with B. burgdorferi, requiring several months of antibiotic therapy, which is an unprecedented treatment approach for a non-life-threatening disease.47 Antibiotics are unique in that their use affects the patient to whom they are prescribed as well as future patients through the generation of new antibiotic-resistant strains of bacteria.48, 49 Our study was limited by the cross-sectional design, thus it is inappropriate to infer causality. Depression and poor affect could be the result of living with chronic symptoms instead of being predisposing factors. Longitudinal studies assessing psychological factors in newly diagnosed Lyme disease patients followed over time could better address these questions. Our comparison group consisted of patients with a variety of medical conditions, which likely results in varying levels of psychiatric comorbidity. Future studies would benefit from evaluating a more homogenous comparison group, for example, only osteoarthritis patients. Also, the accurate assessment of the variables of interest was limited by our questionnaires despite selecting most for their “gold standard” status. Lastly, our Chronic Multisymptom Illness patients may not be representative of others who never ascribed symptoms to “chronic Lyme disease” and received antibiotic treatment. 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49. 49Schiff GD, Wisniewski M, Bult J, et al. Improving inpatient antibiotic prescribing: insights from participation in a national collaborative. Jt Comm J Qual Improv. 2001;27:387–402. MEDLINE a Division of Rheumatology and Connective Tissue Research, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, New Brunswick, NJ b Department of Medicine, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, New Brunswick, NJ c Department of Statistics, Rutgers University, Piscataway, NJ d Lyme Disease Center, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, New Brunswick, NJ e Department of Molecular Genetics & Microbiology, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, New Brunswick, NJ f Pharmaceutical Research Institute, Bristol-Myers Squibb, Princeton, NJ  Requests for reprints should be addressed to Afton L. Hassett, PsyD, UMDNJ-Robert Wood Johnson Medical School, 1 R W Johnson Place MEB-484, New Brunswick, NJ 08903-0019
Funding: The National Institute of Mental Health grant number 1 K08MH65360-01. Conflict of Interest: Afton L. Hassett, PsyD, Principal Investigator and corresponding author: Dr. Hassett does not have any conflicts of interest associated with this study. For full disclosure, Dr. Hassett has other research funded by Bristol-Myers Squibb (BMS) and is a consultant to BMS and Forest Laboratories; however, this study was not funded by either. There is no foreseeable way for her to gain financially by the results reported herein. Diane C. Radvanski, MS, Senior Research Assistant: No conflicts of interest to report. Steven Buyske, PhD, Statistician: Dr. Buyske has no conflicts of interest to report. He does have subcontracts to analyze data related to Dr. Hassett's other research funded by BMS. Shantal V. Savage, BA, Research Assistant: No conflicts of interest to report. Leonard H. Sigal, MD, Senior Author: Dr. Sigal is the Director of the Pharmaceutical Research Institute at Bristol-Myers Squibb (BMS); however, this study was not funded by BMS, and Dr. Sigal does not stand to gain financially by the results reported herein. Authorship: All authors had access to the data and a meaningful role in writing this manuscript. PII: S0002-9343(09)00342-8 doi:10.1016/j.amjmed.2009.02.022 © 2009 Elsevier Inc. All rights reserved. | |
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