- Email: [email protected]
Evaluation of Prospectively Followed Adult Patients with Erythema Migrans Using the Beck Depression Inventory Second Edition
Accepted Manuscript
Evaluation of Prospectively Followed Adult Patients with Erythema Migrans Using the Beck Depression Inventory Second Edition Gary P. Wormser M.D. , Kitae Park B.A. , Colby Madison B.A. , Julia Rozenberg B.A. , Donna McKenna N.P. , Carol Scavarda R.N. , Carol Karmen M.D. , Rhea Dornbush Ph.D. , Paul Visintainer Ph.D. PII: DOI: Reference:
S0002-9343(18)31169-0 https://doi.org/10.1016/j.amjmed.2018.11.039 AJM 14934
To appear in:
The American Journal of Medicine
Please cite this article as: Gary P. Wormser M.D. , Kitae Park B.A. , Colby Madison B.A. , Julia Rozenberg B.A. , Donna McKenna N.P. , Carol Scavarda R.N. , Carol Karmen M.D. , Rhea Dornbush Ph.D. , Paul Visintainer Ph.D. , Evaluation of Prospectively Followed Adult Patients with Erythema Migrans Using the Beck Depression Inventory Second Edition, The American Journal of Medicine (2018), doi: https://doi.org/10.1016/j.amjmed.2018.11.039
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
Evaluation of Prospectively Followed Adult Patients with Erythema Migrans Using the Beck Depression Inventory Second Edition Gary P. Wormser, M.D.1
Colby Madison, B.A.1 Julia Rozenberg, B.A.1 Donna McKenna, N.P.1 Carol Scavarda, R.N.1
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Carol Karmen, M.D.1
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Kitae Park, B.A.1
Rhea Dornbush, Ph.D.2
Paul Visintainer, Ph.D. 3
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Clinical Significance 1. Beck Depression Inventory (BDI-II) scores of early Lyme disease patients were significantly higher than that of matched control subjects at the baseline visit. 2. The baseline score directly correlated with the number of somatic symptoms the Lyme disease patients were experiencing. 3. BDI-II scores of the Lyme disease patients improved over time, with no significant difference in BDI-II scores between patients and controls at both 6 and 12 months.
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From the: 1Division of Infectious Diseases, New York Medical College, Valhalla, NY 10595; 2 Department of Psychiatry, New York Medical College, Valhalla, NY; 3Baystate Medical Center, Springfield, Massachusetts 01199. All authors had access to the data and a role in writing the manuscript.Key words: Lyme; Erythema migrans; Depression; Outcome; Beck Depression Inventory Short title: Evaluation of Lyme Disease Patients for Depression Reprint requests and correspondence: Gary P. Wormser, M.D., New York Medical College, Division of Infectious Diseases, 40 Sunshine Cottage Road, Skyline Office #2N-E14, Valhalla, NY 10595. Phone: 914 493 8865; FAX: 914 594 2461; email: [email protected]
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Abstract Background: The Beck Depression Inventory (BDI-II) may be used to evaluate individuals for symptoms of depression. Methods: In a 1-year prospective study, 52 adult Lyme disease patients with erythema migrans
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and 104 matched control subjects were clinically assessed and completed the BDI-II at study entry and approximately 6 and 12 months later following antibiotic treatment.
Results: The mean BDI-II score was significantly higher at the baseline visit among Lyme
disease patients compared with controls (p=0.002), but no significant differences between the
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groups were observed at either the 6 or 12 month study visits. Over the course of the study, the mean BDI-II scores declined an average of approximately 0.22 points per month (p<0.0005) for Lyme disease patients, whereas the mean scores changed very little for controls (mean change=
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-0.02 per month, p=0.50). The total number of somatic symptoms, out of the 12 symptoms
Lyme disease patients.
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evaluated, strongly and directly correlated with the BDI-II scores at the baseline visit for the
Conclusions: The mean BDI-II scores of patients with early Lyme disease significantly exceeded
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that of matched controls at study entry, but by 6 months the values did not differ significantly.
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There was a good to excellent direct correlation between the BDI-II score and the total number of symptoms, suggesting that the BDI-II scores were reflecting somatic rather than affective
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depressive symptoms. When using the BDI-II as an assessment tool of patients with Lyme disease, infection-related somatic symptoms per se need to be considered in the interpretation of the results.
Lyme disease is the most common tick-borne infection in the United States with approximately 300,000 cases estimated to occur annually [1,2]. Erythema migrans is the earliest 2
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and most frequent clinical manifestation [3,4]. The purpose of this prospective study was to determine whether there is a relationship between early Lyme disease and symptoms consistent with depression. Adult Lyme disease patients with erythema migrans and age, gender, and ethnic group matched controls entered a prospective study and were evaluated at baseline, at
Depression Inventory second edition (BDI-II) [5,6].
Methods
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approximately six months, and at approximately one year after the baseline visit using the Beck
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52 adult patients with erythema migrans, who had no clinical evidence of a concomitant extracutaneous manifestation of Lyme disease, were enrolled in a prospective study to assess the outcome of this infection over a 1 year time frame, as described elsewhere [7]. Each of the
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patients had one or more expanding erythematous skin lesions that were at least 5 cm in diameter [4,8]. For each patient with Lyme disease, two control subjects, who were matched for gender,
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ethnic background and age within 5 years, were recruited during the same Lyme disease season from the primary care internal medicine practice located at the same study site.
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The subjects were evaluated at baseline, at 6 months and at 12 months. At each visit,
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clinical data were collected, including data on which of 12 somatic symptoms were present on the day of the assessment, such as fatigue, headache, joint pain, muscle pain, and cognitive
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complaints, as described elsewhere [7,9]. At each visit the subjects completed the Beck Depression Inventory second edition (BDI-II). The BDI-II is a 21-item self-administered questionnaire focused on current symptoms and symptoms over the preceding 2 weeks [5,6]. Other assessments
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Serologic testing for Lyme disease was performed using the C6 Lyme ELISA kit (Immunetics, Inc., Boston, Massachusetts), according to the manufacturer’s recommendations. Testing was performed at the baseline visit and again at a mean of 16.7 days (range 7-30 days)
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after the baseline visit to look for seroconversion.
Exclusion criteria
Patients were excluded if they had a history of Lyme disease within the prior 12 months, or if they had continuing symptoms from an episode of Lyme disease that occurred more than 1
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year earlier. Control subjects were excluded if they had a prior history of Lyme disease,
irrespective of the time frame. Both Lyme disease patients and control subjects were excluded if they were pregnant, recently post-partum, or immunocompromised; if they had an underlying
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disease or condition that might interfere with evaluation of outcome (e.g., morbid obesity with body mass index > 45; sleep apnea [untreated] and narcolepsy; autoimmune diseases;
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uncontrolled cardiopulmonary or endocrine disorders; malignant conditions within 2 years except for uncomplicated skin cancer; known current liver disease; any past or current diagnosis
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of a major depressive disorder with psychotic or melancholic features; bipolar affective
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disorders; schizophrenia; delusional disorders; dementia; anorexia nervosa or bulimia nervosa; and drug abuse or alcoholism within 2 years). Control subjects underwent 2-tier serologic testing
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for antibodies to Borrelia burgdorferi at the baseline visit, and those found to be seropositive were excluded from the study. The study was conducted at the Lyme Disease Diagnostic Center at New York Medical
College and was approved by the institutional review board at New York Medical College. Statistical methods
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Univariable comparisons of categorical variables were conducted using Fisher’s exact test. Continuous variables were compared by the Student t-test with unequal variances. A multilevel repeated measures regression approach was used to analyze changes in BDI-II scores over time, adjusting for the matching variables (age, gender, and race). The multilevel model
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accounted for the correlated nature of the repeated measurement of BDI-II within individuals over time. Robust standard errors were used to accommodate the skewness of the BDI-II scores. To examine whether changes in BDI-II scores over time differed among cases and controls, we tested the significance of a study group-by-time interaction term using a likelihood ratio test. A
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significant interaction term was followed by post-hoc comparisons of study groups within each time period and between time periods within each study group. Significance testing of post-hoc comparisons was adjusted using Sidak’s approach to account for multiple comparisons.
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Pearson correlation coefficients were used to assess the linear relation between BDI-II scores and the number of somatic symptoms. Correlation coefficients of 0-0.25 were considered to be
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poor; 0.26-0.50 to be fair; 0.51-0.75 to be moderate to good; and >0.75 to be good to excellent
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Results
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[10]. All testing was two-tailed. A p value of <0.05 was considered to be significant.
52 untreated adult patients with erythema migrans and 104 age, gender, and ethnic group
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matched controls (2 to 1) were enrolled into a 1 year prospective study (Table 1). Thirty-one (59.6%) patients had a single erythema migrans skin lesion, and 21 (40.4%) patients had multiple skin lesions. Forty-six (88.5%) of the Lyme disease patients were seropositive by the C6 Lyme ELISA when tested at the baseline visit or within the next 30 days. Thirty-nine (75.0%) of the Lyme disease patients had at least 1 concomitant subjective symptom (out of the 12 symptoms 5
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assessed), such as fatigue, at the baseline visit compared with 53 (51.0%) of the control subjects (p=0.0055). Among those individuals with subjective symptoms at baseline, the number of these symptoms was significantly greater among the Lyme disease patients compared with the control subjects (mean value SD: 4.2 3.1 vs 2.0 1.2, p<0.0005).
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The Lyme disease patients and the matched control subjects were evaluated using the BDI-II at the baseline visit and at approximately 6 and 12 months after the baseline visit. All Lyme disease patients were prescribed an antibiotic regimen regarded as effective for the
treatment of early Lyme disease at the baseline visit [3,4]. All patients and control subjects
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completed the baseline visit. At approximately six months, 46/52 (88.5%) of the Lyme disease patients versus 95/104 (91.3%) of the control subjects (p=0.57) were evaluated, and at approximately 12 months, 49/52 (94.2%) of the Lyme disease patients and 98/104 (94.2%) of the
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control subjects were evaluated (p=1.00).
Scores for the BDI-II were compared between Lyme disease patients and controls at the
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baseline, 6 month and 12 month visits (Table 2). In the unadjusted comparison, the mean BDI-II score was significantly higher at the baseline visit among Lyme disease patients compared with
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controls (p=0.002). However, no significant differences between the groups were observed at
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either 6 months or 12 months. This was due to the decrease for the Lyme disease patients in the mean BDI-II scores from the baseline values at the later time points (at 6 months a reduction of -
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1.3 [p=0.56] and at 12 months a reduction of -2.6 [p<0.006]), whereas among the controls the mean BDI-II scores remained stable over time (-0.4 [p=0.40] between the baseline and 6 month visits, and -0.3 [p=0.78] between the baseline and the 12 month visits). Over the 12-month period, the mean BDI-II scores declined an average of 0.22 points per month (p<0.0005) for Lyme disease patients, whereas the mean scores changed very little for controls (mean change =
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-0.02 per month, p=0.50). Figure 1 shows graphically the changes over time for the study groups. A separate analysis, incorporating the matching variables age, gender, and ethnicity showed similar results. At baseline, the mean BDI-II score for the Lyme disease patients was 2.8
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points higher than the score for the controls (p=0.004). By month 12, the 0.5 difference in mean scores was not significant (p=0.88). The decrease of 2.6 in the mean BDI-II scores between baseline and 12 months for the Lyme disease patients was significant (p=0.006), whereas for controls, the scores remained stable (-0.3; p=0.78). Among Lyme disease patients, BDI-II scores
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decreased an average of 0.22 (95% CI: -0.31, -0.12) points per month (p<0.0005). Little change over time was observed among controls (change per month = -0.02, 95% CI: -0.09, 0.04; p=0.49).
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A further analysis of the BDI-II scores was performed based on a 4-tier categorization in which minimal depression was defined by a score 0-13, mild depression by a score of 14-19,
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moderate depression by a score of 20-28, and severe depression by a score of ≥ 29 [5] (Table 3). At both the baseline and 6 month assessments significantly more of the Lyme disease patients
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had scores consistent with at least mild depression compared with the matched controls (7/52
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[13.5%] vs. 2/104 [1.9%] at baseline, p=0.007; and 4/46 [8.7%] vs 1/95 [1.1%] at 6 months, p=0.039). At 12 months, however, there was no significant difference (3/49 [6.1%] vs 1/98
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[1.0%], p=0.11). In addition, 2 of the 3 Lyme disease patients with BDI-II scores consistent with at least mild depression at the 12 month visit had experienced an intercurrent stressful event unrelated to Lyme disease that was considered to be the explanation for the higher BDI-II scores. The single Lyme disease patient with a score regarded as severe, which was found only at the 6 month visit, was treated by a mental health professional between the 6 and 12 months visits, and
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improved by the 12 month visit. This patient had a prior history of depression when she was pregnant. The total number of somatic symptoms out of the 12 symptoms evaluated strongly and directly correlated with the BDI-II scores at the baseline visit for the Lyme disease patients
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(Table 4). At both 6 and 12 months, there was also a statistically significant but weaker
correlation. Among the control subjects, there was a statistically significant but usually a weaker correlation at each of the 3 time points. To further evaluate the association between the total number of symptoms and the BDI-II scores, a comparison was performed between the 39 Lyme
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disease patients with symptoms at the baseline visit and the 13 patients without any symptoms. The symptomatic patients had significantly higher BDI-II scores compared with those who were asymptomatic (6.5 6.1 [median = 4, range = 0 - 23] vs. 0.8 1.7 [median = 0, range = 0 - 5],
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p<0.0005). In an analysis adjusted for age, gender, and ethnicity, the mean difference in the BDIII scores at the baseline visit for symptomatic versus asymptomatic Lyme disease patients was
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5.5 (95% CI: 2.0-9.0; p=0.003).
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Discussion
The findings in this study demonstrate that the mean BDI-II scores at the baseline visit of
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patients with early Lyme disease significantly exceeded that of age, gender, ethnic group
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matched controls, but by 6 months the values did not differ significantly from the controls. By 12 months the difference in the mean scores was reduced to 0.5. In addition, at the baseline visit there was a good to excellent direct correlation between the BDI-II score and the total number of somatic symptoms, and at the 6 month visit a moderate to good correlation, suggesting that the BDI-II scores may reflect somatic depressive symptoms (which comprise 5 of the 21 items on the BDI-II, i.e., up to a total score value of 15) rather than affective depressive symptoms (which 8
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comprise 16 of the items) [11], as has been demonstrated by other investigators both in patients with early Lyme disease [11] and in patients with hepatitis C [12]. In addition, a comparison of the mean BDI-II scores at the baseline visit for the symptomatic Lyme disease patients far exceeded that of the asymptomatic patients (p<0.0005), a finding that also supports this
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interpretation. Consistent with these observations and other data, the BDI-II should not be regarded, per se, as a diagnostic tool for depression. Instead, it should be thought of as a
screening test to identify patients who might benefit from a psychological referral for further evaluation to assess depression [13].
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The mean values for the BDI-II scores at baseline were similar to those found for another study of early Lyme disease patients (5.1 in our study vs 5.2 in the other study [11]). In our study, BDI-II scores of ≥ 20 among the Lyme disease patients occurred infrequently, 1.9% at
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baseline, 6.5% at six months, and 2.0% at 12 months. By comparison, in a study of over 15,000 college students, 12% had or exceeded this score [14]. Among the three patients with scores of
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≥20 in our study, two were females. In a prior study involving college students, the mean score among females was significantly higher than among males [14].
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Only one of our Lyme disease patients had a BDI-II score at any time point that exceeded
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28. This subject improved after consultation with a mental health professional. This patient also had a prior history of depression while pregnant. By comparison, it has been reported that nearly
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1 out of every 12 adults in the United States will meet criteria for a major depressive episode within a 12 month period [15]. In conclusion, our study found a statistically significantly higher mean BDI-II score
among adult patients with early Lyme disease, compared with age, gender and ethnic group matched controls at the baseline evaluation, but not at 6 months after diagnosis, a finding very
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similar to another recent study [11]. Unlike that prior investigation [11], however, our study extended the evaluation to 12 months after diagnosis and documented a further reduction in the mean BDI-II score among the Lyme disease patients. The significantly higher number of somatic symptoms at the baseline visit, which is expected in patients with infections such as early Lyme
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disease [8], compared with the matched controls appears to be the likely explanation for the significantly higher BDI-II score at this time point. Infection-related symptoms per se need to be considered in the interpretation of the results of studies that incorporate the BDI-II as an
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assessment tool.
References
1. Hinckley AF, Connally NP, Meek JI, Johnson BJ, Kemperman MM, Feldman KA, et al.
Dis 2014; 59:678-681.
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Lyme disease testing by large commercial laboratories in the United States. Clin Infect
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2. Nelson CA, Saha S, Kugeler KJ, Delorey MJ, Shankar MB, Hinckley AF, et al. Incidence of clinician-diagnosed Lyme disease, United States, 2005-2010. Emerg Infect
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Dis 2015; 21:1625-31.
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3. Sanchez E, Vannier E, Wormser GP, Hu LT. Diagnosis, treatment and prevention of Lyme disease, human granulocytic anaplasmosis, and babesiosis: A review. JAMA 2016;
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315:1767-1777.
4. Wormser GP, Dattwyler RJ, Shapiro ED, Halperin JJ, Steere AC, Klempner MS, et al. The clinical assessment, treatment, and prevention of Lyme disease, human granulocytic anaplasmosis, and babesiosis: clinical practice guidelines by the Infectious Diseases Society of America. Clin Infect Dis 2006;43:1089-134.
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5. Beck A, Steer R, Brown G. Beck Depression Inventory second edition manual. San Antonio: The Psychological Corporation. 1996 6. Osman A, Downs WR, Barrios FX, Kopper BA, Gutierrez PM, Chiros CE. Factor structure and psychometric characteristics of the Beck Depression Inventory-II. J
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Psychopathol Behav Assess 1997;19:359. https://doi.org/10.1007/BF02229026
7. Wormser GP, Sudhindra P, Lopez E, Patel L, Rezai S, Brumbaugh AD, et al. Fatigue in patients with erythema migrans. Diagn Microbiol Infect Dis 2016;86:322-326.
8. Tibbles CD, Edlow JA. Does this patient have erythema migrans? JAMA 2007;297:2617-
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27.
9. Weitzner E, McKenna D, Nowakowski J, Scavarda C, Dornbush R, Bittker S, et al. Long-term assessment of post-treatment symptoms in patients with culture-confirmed
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early Lyme disease. Clin Infect Dis 2015;61:1800-1806.
10. Portney LG, Watkins MP. Foundations of Clinical Research: Applications to Practice (3 rd
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Edition). Pearson Education, Inc., Upper Saddle River, NJ., 2009
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11. Bechtold KT, Rebman AW, Crowder LA, Johnson-Greene D, Aucott JN. Standardized symptom measurement of individuals with early Lyme disease over time. Arch Clin
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Neuropsychology 2017;32:129-141.
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12. Patterson AL, Morasco BJ, Fuller BE, Indest DW, Loftis JM, Hauser P. Screening for depression in patients with hepatitis C using the Beck Depression Inventory-II: do somatic symptoms compromise validity? Gen Hosp Psychiatry 2011;33:354-362.
13. Zomer TP, Vermeeren YM, Landman GW, Zwerink M, Van Hees BC, van Bemmel T, van Kosten B. Depressive symptoms in patients referred to a tertiary Lyme center: high 11
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prevalence in those without evidence of Lyme borreliosis. Clin Infect Dis 2017;65:168994. 14. Whisman MA, Richardson ED. Normative data on the Beck depression inventory-
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second edition (BDI-II) in college students. J Clin Psychol 2015;71:898-907. 15. Kessler RC, Birnbaum HG, Shahly V, et al. Age differences in the prevalence and comorbidity of DSM-IV major depressive episodes: Results from the WHO World Mental
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Health Survey Initiative. Depress Anxiety 2010;27:351-364.
Acknowledgments: The authors thank Julia Singer, Sophia Less, Artemio Zavala, Shana
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Warner, and Lisa Giarratano for their assistance.
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Funding: RO1 CK 000152 from the Centers for Disease Control and Prevention (CDC) to GPW. The findings and conclusions of this paper are those of the authors and do not necessarily represent the official position of the CDC.
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Disclosures: Dr. Wormser reports receiving research grants from Immunetics, Inc., Institute for Systems Biology, Rarecyte, Inc., and Quidel Corporation. He owns equity in Abbott/AbbVie; has been an expert witness in malpractice cases involving Lyme disease; and is an unpaid board
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member of the American Lyme Disease Foundation. Other authors have no disclosures.
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Figure 1. The mean (with 95% CI) BDI-II scores of early Lyme disease patients (unbroken line) is compared with of matched controls (dashed line) at baseline, at approximately 6 months and at approximately 12 months after the baseline visit.
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Table 1. Comparison of Selected Demographic Characteristics of Adult Patients with Erythema Migrans and Matched Controls. Lyme Disease Patients 52 50.2 ± 15.7 (50.5, 20-86) 65.4%
Controls 104 50.4 ± 15.0 (52, 20-85) 65.4%
92.3% 7.7%
91.4% 8.6%
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Characteristic Number enrolled Mean age ± SD (median, range) Percent Males Ethnicity Percent Caucasian Percent non-Caucasian
Table 2. Unadjusted and Adjusted Comparison of BDI-II Scores Over Time.
Adjusted1
Unadjusted Lyme disease patients mean (sd)
mean (sd)
Baseline
5.1 (5.9)
2.3 (3.4)
0.002
5.1 (3.5, 6.7)
2.3 (1.6, 3.0)
0.004
6 months
3.8 (7.1)
1.9 (3.5)
0.09
3.8 (1.8, 5.8)
1.9 (1.2, 2.6)
0.19
12 months
2.5 (4.9)
2.0 (3.1)
0.53
2.5 (1.2, 3.9)
2.0 (1.4, 2.6)
0.88
1
p-value
Lyme disease patients mean (95% CI)
Controls
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p-value2
mean (95% CI)
multivariable regression with robust standard errors model adjusted for age, gender, and ethnicity p-values adjusted for multiple comparisons using Sidak’s approach
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Controls
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Time
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Table 3. Categorical Comparisons of Lyme Disease Patients Versus Controls Using BDI-II Scores* Lyme Disease Patients Minimal Mild 45 (86.5%) 6 (11.5%) 42 (91.3%) 1 (2.2%) 46 (93.9%) 2 (4.1%)
Baseline visit 6 month visit 12 month visit
Number evaluable 104 95 98
Matched Controls Minimal Mild 102 (98.1%) 2 (1.9%) 94 (98.9%) 1 (1.1%) 97 (99.0%) 1 (1.0%)
Moderate 1 (1.9%) 2 (4.3%) 1 (2.0%)
Severe 0 (0%) 1 (2.2%) 0 (0%)
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Baseline visit 6 month visit 12 month visit
Number evaluable 52 46 49
Moderate 0 (0%) 0 (0%) 0 (0%)
Severe 0 (0%) 0 (0%) 0 (0%)
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*BDI-II scores consistent with levels of depression: Minimal: 0-13; mild: 14-19; moderate: 2028; severe > 29 Table 4. Correlation Between the Total Number of Symptoms (out of 12 possible) and the BDIII Scores for Patients with Lyme Disease and for Control Subjects. Mean number of symptoms (SD)
Mean BDI-II score (SD)
Number Evaluable
Correlation coefficient
P value
52
0.77
3.8 (7.1)
46
0.65
2.5 (4.9)
49
0.30
< 0.0001 < 0.0001 0.033
6 months
0.8 (1.3)
12 months
1.0 (1.3)
6 months
Control Subjects 2.3 (3.4)
104
0.41
1.1 (1.4)
1.9 (3.5)
95
0.51
0.9 (1.5)
2.0 (3.1)
98
0.47
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12 months
1.0 (1.3)
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Baseline
5.1 (5.9)
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3.1 (3.2)
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Baseline
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Lyme Disease Patients
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< 0.0001 < 0.0001 < 0.0001
Evaluation of Prospectively Followed Adult Patients with Erythema Migrans Using the Beck Depression Inventory Second Edition Gary P. Wormser M.D. , Kitae Park B.A. , Colby Madison B.A. , Julia Rozenberg B.A. , Donna McKenna N.P. , Carol Scavarda R.N. , Carol Karmen M.D. , Rhea Dornbush Ph.D. , Paul Visintainer Ph.D. PII: DOI: Reference:
S0002-9343(18)31169-0 https://doi.org/10.1016/j.amjmed.2018.11.039 AJM 14934
To appear in:
The American Journal of Medicine
Please cite this article as: Gary P. Wormser M.D. , Kitae Park B.A. , Colby Madison B.A. , Julia Rozenberg B.A. , Donna McKenna N.P. , Carol Scavarda R.N. , Carol Karmen M.D. , Rhea Dornbush Ph.D. , Paul Visintainer Ph.D. , Evaluation of Prospectively Followed Adult Patients with Erythema Migrans Using the Beck Depression Inventory Second Edition, The American Journal of Medicine (2018), doi: https://doi.org/10.1016/j.amjmed.2018.11.039
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
Evaluation of Prospectively Followed Adult Patients with Erythema Migrans Using the Beck Depression Inventory Second Edition Gary P. Wormser, M.D.1
Colby Madison, B.A.1 Julia Rozenberg, B.A.1 Donna McKenna, N.P.1 Carol Scavarda, R.N.1
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Carol Karmen, M.D.1
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Kitae Park, B.A.1
Rhea Dornbush, Ph.D.2
Paul Visintainer, Ph.D. 3
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Clinical Significance 1. Beck Depression Inventory (BDI-II) scores of early Lyme disease patients were significantly higher than that of matched control subjects at the baseline visit. 2. The baseline score directly correlated with the number of somatic symptoms the Lyme disease patients were experiencing. 3. BDI-II scores of the Lyme disease patients improved over time, with no significant difference in BDI-II scores between patients and controls at both 6 and 12 months.
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From the: 1Division of Infectious Diseases, New York Medical College, Valhalla, NY 10595; 2 Department of Psychiatry, New York Medical College, Valhalla, NY; 3Baystate Medical Center, Springfield, Massachusetts 01199. All authors had access to the data and a role in writing the manuscript.Key words: Lyme; Erythema migrans; Depression; Outcome; Beck Depression Inventory Short title: Evaluation of Lyme Disease Patients for Depression Reprint requests and correspondence: Gary P. Wormser, M.D., New York Medical College, Division of Infectious Diseases, 40 Sunshine Cottage Road, Skyline Office #2N-E14, Valhalla, NY 10595. Phone: 914 493 8865; FAX: 914 594 2461; email: [email protected]
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Abstract Background: The Beck Depression Inventory (BDI-II) may be used to evaluate individuals for symptoms of depression. Methods: In a 1-year prospective study, 52 adult Lyme disease patients with erythema migrans
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and 104 matched control subjects were clinically assessed and completed the BDI-II at study entry and approximately 6 and 12 months later following antibiotic treatment.
Results: The mean BDI-II score was significantly higher at the baseline visit among Lyme
disease patients compared with controls (p=0.002), but no significant differences between the
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groups were observed at either the 6 or 12 month study visits. Over the course of the study, the mean BDI-II scores declined an average of approximately 0.22 points per month (p<0.0005) for Lyme disease patients, whereas the mean scores changed very little for controls (mean change=
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-0.02 per month, p=0.50). The total number of somatic symptoms, out of the 12 symptoms
Lyme disease patients.
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evaluated, strongly and directly correlated with the BDI-II scores at the baseline visit for the
Conclusions: The mean BDI-II scores of patients with early Lyme disease significantly exceeded
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that of matched controls at study entry, but by 6 months the values did not differ significantly.
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There was a good to excellent direct correlation between the BDI-II score and the total number of symptoms, suggesting that the BDI-II scores were reflecting somatic rather than affective
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depressive symptoms. When using the BDI-II as an assessment tool of patients with Lyme disease, infection-related somatic symptoms per se need to be considered in the interpretation of the results.
Lyme disease is the most common tick-borne infection in the United States with approximately 300,000 cases estimated to occur annually [1,2]. Erythema migrans is the earliest 2
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and most frequent clinical manifestation [3,4]. The purpose of this prospective study was to determine whether there is a relationship between early Lyme disease and symptoms consistent with depression. Adult Lyme disease patients with erythema migrans and age, gender, and ethnic group matched controls entered a prospective study and were evaluated at baseline, at
Depression Inventory second edition (BDI-II) [5,6].
Methods
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approximately six months, and at approximately one year after the baseline visit using the Beck
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52 adult patients with erythema migrans, who had no clinical evidence of a concomitant extracutaneous manifestation of Lyme disease, were enrolled in a prospective study to assess the outcome of this infection over a 1 year time frame, as described elsewhere [7]. Each of the
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patients had one or more expanding erythematous skin lesions that were at least 5 cm in diameter [4,8]. For each patient with Lyme disease, two control subjects, who were matched for gender,
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ethnic background and age within 5 years, were recruited during the same Lyme disease season from the primary care internal medicine practice located at the same study site.
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The subjects were evaluated at baseline, at 6 months and at 12 months. At each visit,
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clinical data were collected, including data on which of 12 somatic symptoms were present on the day of the assessment, such as fatigue, headache, joint pain, muscle pain, and cognitive
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complaints, as described elsewhere [7,9]. At each visit the subjects completed the Beck Depression Inventory second edition (BDI-II). The BDI-II is a 21-item self-administered questionnaire focused on current symptoms and symptoms over the preceding 2 weeks [5,6]. Other assessments
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Serologic testing for Lyme disease was performed using the C6 Lyme ELISA kit (Immunetics, Inc., Boston, Massachusetts), according to the manufacturer’s recommendations. Testing was performed at the baseline visit and again at a mean of 16.7 days (range 7-30 days)
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after the baseline visit to look for seroconversion.
Exclusion criteria
Patients were excluded if they had a history of Lyme disease within the prior 12 months, or if they had continuing symptoms from an episode of Lyme disease that occurred more than 1
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year earlier. Control subjects were excluded if they had a prior history of Lyme disease,
irrespective of the time frame. Both Lyme disease patients and control subjects were excluded if they were pregnant, recently post-partum, or immunocompromised; if they had an underlying
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disease or condition that might interfere with evaluation of outcome (e.g., morbid obesity with body mass index > 45; sleep apnea [untreated] and narcolepsy; autoimmune diseases;
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uncontrolled cardiopulmonary or endocrine disorders; malignant conditions within 2 years except for uncomplicated skin cancer; known current liver disease; any past or current diagnosis
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of a major depressive disorder with psychotic or melancholic features; bipolar affective
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disorders; schizophrenia; delusional disorders; dementia; anorexia nervosa or bulimia nervosa; and drug abuse or alcoholism within 2 years). Control subjects underwent 2-tier serologic testing
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for antibodies to Borrelia burgdorferi at the baseline visit, and those found to be seropositive were excluded from the study. The study was conducted at the Lyme Disease Diagnostic Center at New York Medical
College and was approved by the institutional review board at New York Medical College. Statistical methods
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Univariable comparisons of categorical variables were conducted using Fisher’s exact test. Continuous variables were compared by the Student t-test with unequal variances. A multilevel repeated measures regression approach was used to analyze changes in BDI-II scores over time, adjusting for the matching variables (age, gender, and race). The multilevel model
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accounted for the correlated nature of the repeated measurement of BDI-II within individuals over time. Robust standard errors were used to accommodate the skewness of the BDI-II scores. To examine whether changes in BDI-II scores over time differed among cases and controls, we tested the significance of a study group-by-time interaction term using a likelihood ratio test. A
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significant interaction term was followed by post-hoc comparisons of study groups within each time period and between time periods within each study group. Significance testing of post-hoc comparisons was adjusted using Sidak’s approach to account for multiple comparisons.
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Pearson correlation coefficients were used to assess the linear relation between BDI-II scores and the number of somatic symptoms. Correlation coefficients of 0-0.25 were considered to be
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poor; 0.26-0.50 to be fair; 0.51-0.75 to be moderate to good; and >0.75 to be good to excellent
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Results
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[10]. All testing was two-tailed. A p value of <0.05 was considered to be significant.
52 untreated adult patients with erythema migrans and 104 age, gender, and ethnic group
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matched controls (2 to 1) were enrolled into a 1 year prospective study (Table 1). Thirty-one (59.6%) patients had a single erythema migrans skin lesion, and 21 (40.4%) patients had multiple skin lesions. Forty-six (88.5%) of the Lyme disease patients were seropositive by the C6 Lyme ELISA when tested at the baseline visit or within the next 30 days. Thirty-nine (75.0%) of the Lyme disease patients had at least 1 concomitant subjective symptom (out of the 12 symptoms 5
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assessed), such as fatigue, at the baseline visit compared with 53 (51.0%) of the control subjects (p=0.0055). Among those individuals with subjective symptoms at baseline, the number of these symptoms was significantly greater among the Lyme disease patients compared with the control subjects (mean value SD: 4.2 3.1 vs 2.0 1.2, p<0.0005).
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The Lyme disease patients and the matched control subjects were evaluated using the BDI-II at the baseline visit and at approximately 6 and 12 months after the baseline visit. All Lyme disease patients were prescribed an antibiotic regimen regarded as effective for the
treatment of early Lyme disease at the baseline visit [3,4]. All patients and control subjects
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completed the baseline visit. At approximately six months, 46/52 (88.5%) of the Lyme disease patients versus 95/104 (91.3%) of the control subjects (p=0.57) were evaluated, and at approximately 12 months, 49/52 (94.2%) of the Lyme disease patients and 98/104 (94.2%) of the
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control subjects were evaluated (p=1.00).
Scores for the BDI-II were compared between Lyme disease patients and controls at the
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baseline, 6 month and 12 month visits (Table 2). In the unadjusted comparison, the mean BDI-II score was significantly higher at the baseline visit among Lyme disease patients compared with
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controls (p=0.002). However, no significant differences between the groups were observed at
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either 6 months or 12 months. This was due to the decrease for the Lyme disease patients in the mean BDI-II scores from the baseline values at the later time points (at 6 months a reduction of -
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1.3 [p=0.56] and at 12 months a reduction of -2.6 [p<0.006]), whereas among the controls the mean BDI-II scores remained stable over time (-0.4 [p=0.40] between the baseline and 6 month visits, and -0.3 [p=0.78] between the baseline and the 12 month visits). Over the 12-month period, the mean BDI-II scores declined an average of 0.22 points per month (p<0.0005) for Lyme disease patients, whereas the mean scores changed very little for controls (mean change =
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-0.02 per month, p=0.50). Figure 1 shows graphically the changes over time for the study groups. A separate analysis, incorporating the matching variables age, gender, and ethnicity showed similar results. At baseline, the mean BDI-II score for the Lyme disease patients was 2.8
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points higher than the score for the controls (p=0.004). By month 12, the 0.5 difference in mean scores was not significant (p=0.88). The decrease of 2.6 in the mean BDI-II scores between baseline and 12 months for the Lyme disease patients was significant (p=0.006), whereas for controls, the scores remained stable (-0.3; p=0.78). Among Lyme disease patients, BDI-II scores
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decreased an average of 0.22 (95% CI: -0.31, -0.12) points per month (p<0.0005). Little change over time was observed among controls (change per month = -0.02, 95% CI: -0.09, 0.04; p=0.49).
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A further analysis of the BDI-II scores was performed based on a 4-tier categorization in which minimal depression was defined by a score 0-13, mild depression by a score of 14-19,
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moderate depression by a score of 20-28, and severe depression by a score of ≥ 29 [5] (Table 3). At both the baseline and 6 month assessments significantly more of the Lyme disease patients
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had scores consistent with at least mild depression compared with the matched controls (7/52
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[13.5%] vs. 2/104 [1.9%] at baseline, p=0.007; and 4/46 [8.7%] vs 1/95 [1.1%] at 6 months, p=0.039). At 12 months, however, there was no significant difference (3/49 [6.1%] vs 1/98
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[1.0%], p=0.11). In addition, 2 of the 3 Lyme disease patients with BDI-II scores consistent with at least mild depression at the 12 month visit had experienced an intercurrent stressful event unrelated to Lyme disease that was considered to be the explanation for the higher BDI-II scores. The single Lyme disease patient with a score regarded as severe, which was found only at the 6 month visit, was treated by a mental health professional between the 6 and 12 months visits, and
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improved by the 12 month visit. This patient had a prior history of depression when she was pregnant. The total number of somatic symptoms out of the 12 symptoms evaluated strongly and directly correlated with the BDI-II scores at the baseline visit for the Lyme disease patients
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(Table 4). At both 6 and 12 months, there was also a statistically significant but weaker
correlation. Among the control subjects, there was a statistically significant but usually a weaker correlation at each of the 3 time points. To further evaluate the association between the total number of symptoms and the BDI-II scores, a comparison was performed between the 39 Lyme
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disease patients with symptoms at the baseline visit and the 13 patients without any symptoms. The symptomatic patients had significantly higher BDI-II scores compared with those who were asymptomatic (6.5 6.1 [median = 4, range = 0 - 23] vs. 0.8 1.7 [median = 0, range = 0 - 5],
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p<0.0005). In an analysis adjusted for age, gender, and ethnicity, the mean difference in the BDIII scores at the baseline visit for symptomatic versus asymptomatic Lyme disease patients was
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5.5 (95% CI: 2.0-9.0; p=0.003).
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Discussion
The findings in this study demonstrate that the mean BDI-II scores at the baseline visit of
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patients with early Lyme disease significantly exceeded that of age, gender, ethnic group
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matched controls, but by 6 months the values did not differ significantly from the controls. By 12 months the difference in the mean scores was reduced to 0.5. In addition, at the baseline visit there was a good to excellent direct correlation between the BDI-II score and the total number of somatic symptoms, and at the 6 month visit a moderate to good correlation, suggesting that the BDI-II scores may reflect somatic depressive symptoms (which comprise 5 of the 21 items on the BDI-II, i.e., up to a total score value of 15) rather than affective depressive symptoms (which 8
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comprise 16 of the items) [11], as has been demonstrated by other investigators both in patients with early Lyme disease [11] and in patients with hepatitis C [12]. In addition, a comparison of the mean BDI-II scores at the baseline visit for the symptomatic Lyme disease patients far exceeded that of the asymptomatic patients (p<0.0005), a finding that also supports this
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interpretation. Consistent with these observations and other data, the BDI-II should not be regarded, per se, as a diagnostic tool for depression. Instead, it should be thought of as a
screening test to identify patients who might benefit from a psychological referral for further evaluation to assess depression [13].
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The mean values for the BDI-II scores at baseline were similar to those found for another study of early Lyme disease patients (5.1 in our study vs 5.2 in the other study [11]). In our study, BDI-II scores of ≥ 20 among the Lyme disease patients occurred infrequently, 1.9% at
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baseline, 6.5% at six months, and 2.0% at 12 months. By comparison, in a study of over 15,000 college students, 12% had or exceeded this score [14]. Among the three patients with scores of
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≥20 in our study, two were females. In a prior study involving college students, the mean score among females was significantly higher than among males [14].
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Only one of our Lyme disease patients had a BDI-II score at any time point that exceeded
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28. This subject improved after consultation with a mental health professional. This patient also had a prior history of depression while pregnant. By comparison, it has been reported that nearly
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1 out of every 12 adults in the United States will meet criteria for a major depressive episode within a 12 month period [15]. In conclusion, our study found a statistically significantly higher mean BDI-II score
among adult patients with early Lyme disease, compared with age, gender and ethnic group matched controls at the baseline evaluation, but not at 6 months after diagnosis, a finding very
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similar to another recent study [11]. Unlike that prior investigation [11], however, our study extended the evaluation to 12 months after diagnosis and documented a further reduction in the mean BDI-II score among the Lyme disease patients. The significantly higher number of somatic symptoms at the baseline visit, which is expected in patients with infections such as early Lyme
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disease [8], compared with the matched controls appears to be the likely explanation for the significantly higher BDI-II score at this time point. Infection-related symptoms per se need to be considered in the interpretation of the results of studies that incorporate the BDI-II as an
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assessment tool.
References
1. Hinckley AF, Connally NP, Meek JI, Johnson BJ, Kemperman MM, Feldman KA, et al.
Dis 2014; 59:678-681.
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Lyme disease testing by large commercial laboratories in the United States. Clin Infect
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2. Nelson CA, Saha S, Kugeler KJ, Delorey MJ, Shankar MB, Hinckley AF, et al. Incidence of clinician-diagnosed Lyme disease, United States, 2005-2010. Emerg Infect
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Dis 2015; 21:1625-31.
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3. Sanchez E, Vannier E, Wormser GP, Hu LT. Diagnosis, treatment and prevention of Lyme disease, human granulocytic anaplasmosis, and babesiosis: A review. JAMA 2016;
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315:1767-1777.
4. Wormser GP, Dattwyler RJ, Shapiro ED, Halperin JJ, Steere AC, Klempner MS, et al. The clinical assessment, treatment, and prevention of Lyme disease, human granulocytic anaplasmosis, and babesiosis: clinical practice guidelines by the Infectious Diseases Society of America. Clin Infect Dis 2006;43:1089-134.
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5. Beck A, Steer R, Brown G. Beck Depression Inventory second edition manual. San Antonio: The Psychological Corporation. 1996 6. Osman A, Downs WR, Barrios FX, Kopper BA, Gutierrez PM, Chiros CE. Factor structure and psychometric characteristics of the Beck Depression Inventory-II. J
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Psychopathol Behav Assess 1997;19:359. https://doi.org/10.1007/BF02229026
7. Wormser GP, Sudhindra P, Lopez E, Patel L, Rezai S, Brumbaugh AD, et al. Fatigue in patients with erythema migrans. Diagn Microbiol Infect Dis 2016;86:322-326.
8. Tibbles CD, Edlow JA. Does this patient have erythema migrans? JAMA 2007;297:2617-
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27.
9. Weitzner E, McKenna D, Nowakowski J, Scavarda C, Dornbush R, Bittker S, et al. Long-term assessment of post-treatment symptoms in patients with culture-confirmed
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early Lyme disease. Clin Infect Dis 2015;61:1800-1806.
10. Portney LG, Watkins MP. Foundations of Clinical Research: Applications to Practice (3 rd
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Edition). Pearson Education, Inc., Upper Saddle River, NJ., 2009
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11. Bechtold KT, Rebman AW, Crowder LA, Johnson-Greene D, Aucott JN. Standardized symptom measurement of individuals with early Lyme disease over time. Arch Clin
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Neuropsychology 2017;32:129-141.
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12. Patterson AL, Morasco BJ, Fuller BE, Indest DW, Loftis JM, Hauser P. Screening for depression in patients with hepatitis C using the Beck Depression Inventory-II: do somatic symptoms compromise validity? Gen Hosp Psychiatry 2011;33:354-362.
13. Zomer TP, Vermeeren YM, Landman GW, Zwerink M, Van Hees BC, van Bemmel T, van Kosten B. Depressive symptoms in patients referred to a tertiary Lyme center: high 11
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prevalence in those without evidence of Lyme borreliosis. Clin Infect Dis 2017;65:168994. 14. Whisman MA, Richardson ED. Normative data on the Beck depression inventory-
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second edition (BDI-II) in college students. J Clin Psychol 2015;71:898-907. 15. Kessler RC, Birnbaum HG, Shahly V, et al. Age differences in the prevalence and comorbidity of DSM-IV major depressive episodes: Results from the WHO World Mental
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Health Survey Initiative. Depress Anxiety 2010;27:351-364.
Acknowledgments: The authors thank Julia Singer, Sophia Less, Artemio Zavala, Shana
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Warner, and Lisa Giarratano for their assistance.
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Funding: RO1 CK 000152 from the Centers for Disease Control and Prevention (CDC) to GPW. The findings and conclusions of this paper are those of the authors and do not necessarily represent the official position of the CDC.
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Disclosures: Dr. Wormser reports receiving research grants from Immunetics, Inc., Institute for Systems Biology, Rarecyte, Inc., and Quidel Corporation. He owns equity in Abbott/AbbVie; has been an expert witness in malpractice cases involving Lyme disease; and is an unpaid board
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member of the American Lyme Disease Foundation. Other authors have no disclosures.
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Figure 1. The mean (with 95% CI) BDI-II scores of early Lyme disease patients (unbroken line) is compared with of matched controls (dashed line) at baseline, at approximately 6 months and at approximately 12 months after the baseline visit.
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Table 1. Comparison of Selected Demographic Characteristics of Adult Patients with Erythema Migrans and Matched Controls. Lyme Disease Patients 52 50.2 ± 15.7 (50.5, 20-86) 65.4%
Controls 104 50.4 ± 15.0 (52, 20-85) 65.4%
92.3% 7.7%
91.4% 8.6%
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Characteristic Number enrolled Mean age ± SD (median, range) Percent Males Ethnicity Percent Caucasian Percent non-Caucasian
Table 2. Unadjusted and Adjusted Comparison of BDI-II Scores Over Time.
Adjusted1
Unadjusted Lyme disease patients mean (sd)
mean (sd)
Baseline
5.1 (5.9)
2.3 (3.4)
0.002
5.1 (3.5, 6.7)
2.3 (1.6, 3.0)
0.004
6 months
3.8 (7.1)
1.9 (3.5)
0.09
3.8 (1.8, 5.8)
1.9 (1.2, 2.6)
0.19
12 months
2.5 (4.9)
2.0 (3.1)
0.53
2.5 (1.2, 3.9)
2.0 (1.4, 2.6)
0.88
1
p-value
Lyme disease patients mean (95% CI)
Controls
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p-value2
mean (95% CI)
multivariable regression with robust standard errors model adjusted for age, gender, and ethnicity p-values adjusted for multiple comparisons using Sidak’s approach
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2
Controls
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Time
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Table 3. Categorical Comparisons of Lyme Disease Patients Versus Controls Using BDI-II Scores* Lyme Disease Patients Minimal Mild 45 (86.5%) 6 (11.5%) 42 (91.3%) 1 (2.2%) 46 (93.9%) 2 (4.1%)
Baseline visit 6 month visit 12 month visit
Number evaluable 104 95 98
Matched Controls Minimal Mild 102 (98.1%) 2 (1.9%) 94 (98.9%) 1 (1.1%) 97 (99.0%) 1 (1.0%)
Moderate 1 (1.9%) 2 (4.3%) 1 (2.0%)
Severe 0 (0%) 1 (2.2%) 0 (0%)
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Baseline visit 6 month visit 12 month visit
Number evaluable 52 46 49
Moderate 0 (0%) 0 (0%) 0 (0%)
Severe 0 (0%) 0 (0%) 0 (0%)
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*BDI-II scores consistent with levels of depression: Minimal: 0-13; mild: 14-19; moderate: 2028; severe > 29 Table 4. Correlation Between the Total Number of Symptoms (out of 12 possible) and the BDIII Scores for Patients with Lyme Disease and for Control Subjects. Mean number of symptoms (SD)
Mean BDI-II score (SD)
Number Evaluable
Correlation coefficient
P value
52
0.77
3.8 (7.1)
46
0.65
2.5 (4.9)
49
0.30
< 0.0001 < 0.0001 0.033
6 months
0.8 (1.3)
12 months
1.0 (1.3)
6 months
Control Subjects 2.3 (3.4)
104
0.41
1.1 (1.4)
1.9 (3.5)
95
0.51
0.9 (1.5)
2.0 (3.1)
98
0.47
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12 months
1.0 (1.3)
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Baseline
5.1 (5.9)
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3.1 (3.2)
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Baseline
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Lyme Disease Patients
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< 0.0001 < 0.0001 < 0.0001