Presence of depression and anxiety with distinct patterns of pharmacological treatments before the diagnosis of chronic fatigue syndrome: a population-based study in Taiwan
verfasst von:
Chi Chen, Hei-Tung Yip, Kam-Hang Leong, Wei-Cheng Yao, Chung-Lieh Hung, Ching-Huang Su, Chien-Feng Kuo, Shin-Yi Tsai
An increased prevalence of psychiatric comorbidities (including depression and anxiety disorder) has been observed among patients with chronic fatigue syndrome (CFS). However, few studies have examined the presence of depression and anxiety disorder before the diagnosis of CFS. This study aimed to clarify the preexisting comorbidities and treatments associated with patients with subsequent CFS diagnosis in a population-based cohort in Taiwan.
Methods
An analysis utilizing the National Health Insurance Research Database of Taiwan was conducted. Participants included were 6303 patients with CFS newly diagnosed between 2000 and 2010 and 6303 age-/sex-matched controls.
Results
Compared with the control group, the CFS group had a higher prevalence of depression and anxiety disorder before the diagnosis of CFS. Sampled patients who took specific types of antidepressants, namely, selective serotonin reuptake inhibitors (adjusted odds ratio [aOR] = 1.21, 95% confidence interval [CI] 1.04–1.39), serotonin antagonists and reuptake inhibitors (SARI; aOR = 1.87, 95% CI 1.59–2.19), and tricyclic antidepressants (aOR = 1.46, 95% CI 1.09–1.95), had an increased risk of CFS. CFS risk was also higher among participants taking benzodiazepine, muscle relaxants, and analgesic drugs. A sub-group analysis revealed that SARI use was related to an increased risk of CFS in the depression, anxiety disorder, male, and female groups. In the depression and anxiety disorder groups, analgesic drug use was associated with an increased CFS risk. Nonpharmacological treatment administration differed between men and women.
Conclusion
This population-based retrospective cohort study revealed an increased risk of CFS among populations with preexisting depression and anxiety disorder, especially those taking SARI and analgesic drugs.
Chi Chen, Kam-Hang Leong, and Wei-Cheng Yao are joint first authors contributed equally to this work
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Introduction
Patients with chronic fatigue syndrome (CFS) experience prolonged and disabling fatigue that cannot be explained with the existing state of medical knowledge. The prevalence of CFS differs widely depending on the diagnostic criteria, assessment method, and studied population, with its numbers ranging from 0.2% to 6.41% [1, 2]. A systematic review of 46 studies in 2020 estimated a CFS prevalence rate of 0.89% on the basis of the commonly used Centers for Disease Control (CDC)-1994 definition of CFS [3, 4]. The aforementioned review also reported a sex difference, with female individuals having prevalence rates that were 1.5 to 2 times higher than those of male individuals.
In addition to fatigue, several accompanying symptoms were also frequently reported, specifically muscle pain, multiple joint pain, poor sleep, anxiety, and depression [5]. Musculoskeletal pain and insomnia were included in the CDC-1994 diagnostic criteria. Furthermore, mood and anxiety disorders were reported to be more prevalent in individuals with CFS relative to the general population [6]. CFS, which is also known as myalgic encephalomyelitis, had found to be potentially related with immune processes such as inflammation and infection [7]. Recent comparisons between the similarities of CFS and the potential COVID-19 long-term effects, including persistent fatigue, postexertional malaise and pain, had underlined the critical role of the immune response in such conditions [8, 9]. On the other hand, the systemic inflammation may be the mediator of CFS and its psychiatric comorbidities [10, 11]. It is notable that the relationship between CFS and psychiatric comorbidities might be bidirectional as an abnormal immune response has also been demonstrated among the patients with depression or anxiety disorder [12‐14]. A study investigated patients with CFS and reported that the prevalence rates of concurrent anxiety and depression were 42.2% and 33.3%, respectively [15]. However, few large-scale epidemiological investigations of psychiatric comorbidities, especially those that focused on Asian populations, have been conducted.
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With a focus on CFS, depression, and anxiety, this population-based retrospective cohort study investigated and analyzed the data from the Taiwan National Health Insurance Research Database (NHIRD). The treatments received by participants were also further analyzed by sex, age, and comorbidities.
Methods
Data resource
The dataset used in this study were derived from the National Health Insurance Research Database (NHIRD) in Taiwan. The National Health Insurance (NHI) program was launched on March 1, 1995, by Taiwan’s government. NHIRD has contained details concerning the demographic characteristics, dates of admission and discharge, prescriptions, surgical procedures, and diagnostic codes for approximately 99% of the entire population of the 23 million people residing in Taiwan. We used the 2000 Longitudinal Health Insurance Database (LHID) which was established by NHIRD. LHID 2000 was created and released to the public by NHIRD and includes all the original claim data and registration files between 2000 and 2013 for one million individuals randomly sampled from the Registry for beneficiaries of the NHI program in 2000 in Taiwan. The diseases are defined according to the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM).
Sample participants
Cases of CFS were identified using two outpatient records or one admission record with a diagnosis of ICD-9-CM code 780.71. The date of the first diagnosed record of chronic fatigue syndrome was defined as the index date. For each chronic fatigue syndrome case, we used a frequency matching method and randomly selected one control without chronic fatigue syndrome diagnosis. The dataset for the control population of 1 million samples was randomly selected from the LHI dataset, and individuals without a diagnosis of CFS were selected as the control population with the same sex, age, and index date. (Fig. 1.) We excluded the participants aged below 18 years or with missing information on sex. In the ICD-9-CM, the diagnosis of CFS is mainly based on the CDC-1994 diagnostic criteria noted in the ICD-9-CM Coordination and Maintenance Committee Meeting in 2011. The CDC-1994 diagnostic criteria specifically defined the patients receiving appropriate treatment for depression or anxiety, the diagnosis could still be made among patients with premorbid depression or anxiety [3].
Fig. 1
The participants selecting process in the cohort study
×
Exposure assessment and comorbidities
For this study, we examined the exposure of pharmaceutical and non-pharmaceutical treatments. We accounted the exposure to pharmaceutical treatments of SSRI drugs (ATC code N06AB10, N06AB06, N06AB03, and N06AB08), SNRI drugs (ATC code N06AX21, and N06AX16), SARI drugs (ATC code N06AX05), norepinephrine and dopamine reuptake inhibitor (NDRI) drug (ATC code N06AX12), noradrenergic and specific serotonergic antidepressants (NaSSA) drug (N06AX11), TCAs drugs (ATC code N06AA09 and N06CA01), BZD drugs (ATC code N03AE01, N05BA06, N05BA12, N05BA01, N05BA17, N05BA22, N05CD04, N05CD05, N05CD03, N05CD09, N05CD01, N05CD08), muscle relaxant (ATC code M03BX08), analgesic drugs which including acetaminophen, NSAIDs, pregabalin, gabapentin (ATC code M02AA, D11AX18, M01A, M01B, N03AX16, and N03AX12) and non-pharmaceutical of support psychotherapy, supportive group psychotherapy, deep psychotherapy, in-depth group psychotherapy, special psychotherapy, special group psychotherapy, behavioral therapy evaluation, behavioral therapy plan, supportive psychosocial consultation for family members/caregivers, stretching exercise, exercise therapy, breathing exercise, induced deep breathing exercise, rehabilitation exercise, multiple physical examinations of sleep, brainwave examination, sleep or wakefulness, and brainwave examination for sleep disorders. Study participants were categorized based on their pharmaceutical and non-pharmaceutical exposure status. Patients exposed to pharmaceutical or non-pharmaceutical were classified as users or non-users. We adjusted for the potentially confounding effects of other comorbidities, including depression (ICD-9-CM code 296.2, 296.3, 926.82, 300.4, 309.0, 309.1, and 311), anxiety disorder (ICD-9-CM code 300.0–300.3, 300.5–300.9, 309.2–309.4, 309.81, and 313.0), insomnia (ICD-9-CM code 307.41, 307.42, 780.50, and 780.52), suicide (ICD-9-CM code E950-E959), Crohn’s disease (ICD-9-CM code 555), ulcerative colitis (ICD-9-CM code 555–556), renal disease (ICD-9-CM code 580–589), diabetes mellitus (ICD-9-CM code 250 and A181), obesity (ICD-9-CM code 278), gout (ICD-9-CM code 274), dyslipidemia (ICD-9-CM code 272), malignancy (ICD-9-CM code 140–208), HIV (ICD-9-CM code 042–044), rheumatoid arthritis (ICD-9-CM code 714), psoriasis (ICD-9-CM code 696.x), ankylosing spondylitis (ICD-9-CM code 720.0), lymphadenopathy (ICD-9-CM code 289.1–289.3, 686, and 785.6), Hashimoto's thyroiditis (ICD-9-CM code 245.2), Sjogren's syndrome (ICD-9-CM code 710.2), irritable bowel syndrome (ICD-9-CM code 564.1), SLE (ICD-9-CM code 710.0), celiac disease (ICD-9-CM code 579.00, and herpes zoster (ICD-9-CM code 053) prior to the index date were evaluated as part of the analysis.
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Statistical analysis
Descriptive statistics of CFS and controls are reported, including demographic characteristics, comorbid diseases, and exposure to potentially confounding treatments. The chi-square test was used to compare categorical variables, whereas the Student’s t-test was used to compare continuous variables between chronic fatigue syndrome cohort and comparison cohort as necessary. We used conditional logistic regression to assess the risk of CFS according to each category of pharmaceutical and non-pharmaceutical. The odds ratio (ORs) and 95% confidence intervals (CIs) for CFS were calculated as an unadjusted incidence rate, and then subsequently adjusted for covariates including age, sex, comorbidities, pharmaceutical and non-pharmaceutical. Bonferroni correction was performed for the correction of multiple comparisons. Analyses were performed using SAS software (version 9.4 for windows; SAS Institute, Cary, NC, USA) for Windows 10. All statistical significance levels were set at a p < 0.05.
Results
This study included 6306 patients with CFS and 6306 patients without, all of whom were identified from the NHIRD between January 1, 2000, and December 31, 2013. The demographic and clinical characteristics of the study participants are presented in Table 1. Among the participants, 52.9 were female, and most were between 25 and 64 years old; the mean age of the participants was 50.6 years. With regard to the prevalence of comorbidities, participants with CFS had higher numbers of psychiatric disorders (depression, anxiety disorder, and insomnia), irritable bowel syndrome, inflammatory bowel diseases (Crohn’s disease and ulcerative colitis), autoimmune disorders (rheumatoid arthritis, and Sjogren’s syndrome), metabolic disorders (type 2 diabetes mellitus, gout, and dyslipidemia), and renal disease (all p < 0.005).
Table 1
Demographic characteristics and comorbidities of patients newly diagnosed with or without chronic fatigue syndrome in Taiwan during 2000–2010
Variable
CFS cohort
Non-CFS cohort
P-value
(n = 6306)
(n = 6306)
Gender
> 0.99
Female
3339 (52.9)
3339 (52.9)
Male
2967 (47.1)
2967 (47.1)
Age at diagnosis of CFS
> 0.99
≤ 34
1350 (21.4)
1350 (21.4)
35–64
3485 (55.3)
3485 (55.3)
≥ 65
1471 (23.3)
1471 (23.3)
Age at diagnosis of CFS(mean, SD)†
50.6 (17.9)
50.6 (18.0)
0.80
Comorbidity
Depression
807 (12.8)
407 (6.45)
< 0.0001
Anxiety disorder
2038 (32.3)
1033 (16.4)
< 0.0001
Insomnia
2303 (36.5)
1106 (17.5)
< 0.0001
Irritable bowel syndrome
886 (14.1)
423 (6.71)
< 0.0001
Crohn's disease
255 (4.04)
121 (1.92)
< 0.0001
Ulcerative colitis
279 (4.42)
138 (2.19)
< 0.0001
Rheumatoid arthritis
254 (4.03)
155 (2.46)
< 0.0001
Sjogren's syndrome
110 (1.74)
71 (1.13)
0.003
Psoriasis
94 (1.49)
83 (1.32)
0.40
Ankylosing spondylitis
53 (0.84)
39 (0.62)
0.14
Hashimoto's thyroiditis
13 (0.21)
10 (0.16)
0.53
T1DM
78 (1.24)
68 (1.08)
0.40
T2DM
1473 (23.3)
1068 (16.9)
< 0.0001
Gout
1196 (18.9)
702 (11.1)
< 0.0001
Dyslipidemia
2252 (35.7)
1356 (21.5)
< 0.0001
Renal disease
585 (9.28)
427 (6.77)
< 0.0001
CFS chronic fatigue syndrome, T1DM type 1 diabetes mellitus, T2DM type 2 diabetes mellitus, SD standard deviation
†Student’s t-test
Table 2 and Fig. 2 shows the pharmacological and no-pharmacological treatment received before the diagnosis of CFS. Participants taking certain types of antidepressants, including SSRI, SARI, and TCA, had higher odds of CSF, with the adjusted odds ratio (aORs) of 1.21 (95% CI 1.04–1.39), 1.87 (95% CI 1.59–2.19), and 1.46 (95% CI 1.09–1.95). Other drugs with increased aORs of CFS included BZDs (1.60, 95% CI 1.46–1.76), muscle relaxants (1.74, 95% CI 1.39–2.19), and analgesics (3.56, 95% CI 3.16–4). As for the non-pharmacological treatments and examinations received by the participants, undergoing brainwave examination had a significantly increased odds ratio (1.6, 95% CI 1.44–1.77) of CFS but an insignificant aOR after being adjusted with demographic data and comorbidities.
Table 2
Conditional logical regression measured odds ratios of chronic fatigue syndrome with different treatments
Variable
N
Control
CFS
Odds ratio
Multiple comparisons
n
%
n
%
Crude (95% CI)
p-value
Adjusted (95% CI)
p-value
p-value
SSRI
1.90 (1.68,2.14)***
< 0.001
1.21 (1.04,1.39)*
0.011
0.001
No
11,365
5858
52%
5507
48%
Yes
1247
448
36%
799
64%
SNRI
2.11 (1.65,2.70)***
< 0.001
1.27 (0.97,1.67)
0.080
0.006
No
12,320
6211
50%
6109
50%
Yes
292
95
33%
197
67%
SARI
2.85 (2.46,3.31)***
< 0.001
1.87 (1.59,2.19)***
< 0.001
< 0.001
No
11,684
6052
52%
5632
48%
Yes
928
254
27%
674
73%
TCAs
2.04 (1.55,2.68)***
< 0.001
1.46 (1.09,1.95)**
0.010
0.001
No
12,374
6227
50%
6147
50%
Yes
238
79
33%
159
67%
NDRI
1.85 (1.20,2.85)**
0.005
0.85 (0.53,1.36)
0.495
0.035
No
12,521
6274
50%
6247
50%
Yes
91
32
35%
59
65%
NaSSA
2.04 (1.51,2.74)***
< 0.001
1.12 (0.81,1.54)
0.508
0.036
No
12,413
6240
50%
6173
50%
Yes
199
66
33%
133
67%
BZD
2.14 (1.98,2.32)***
< 0.001
1.60 (1.46,1.76)***
< 0.001
< 0.001
No
3680
2328
63%
1352
37%
Yes
8932
3978
45%
4954
55%
Muscle relaxant
2.16 (1.74,2.69)***
< 0.001
1.74 (1.39,2.19)***
< 0.001
< 0.001
No
12,229
6183
51%
6046
49%
Yes
383
123
32%
260
68%
Analgesic drug
4.43 (3.96,4.97)***
< 0.001
3.56 (3.16,4.00)***
< 0.001
< 0.001
No
1995
1560
78%
435
22%
Yes
10,617
4746
45%
5871
55%
Supportive individual psychotherapy
1.10 (0.94,1.29)
0.229
1.09 (0.92,1.29)
0.302
0.022
No
11,956
5993
50%
5963
50%
Yes
656
313
48%
343
52%
Re-educative group psychotherapy
0.60 (0.33,1.08)
0.086
0.56 (0.30,1.04)
0.065
0.005
No
12,564
6276
50%
6288
50%
Yes
48
30
63%
18
38%
Stretching exercise
1.08 (0.94,1.25)
0.280
1.07 (0.92,1.24)
0.367
0.026
No
11,788
5909
50%
5879
50%
Yes
824
397
48%
427
52%
Therapeutic exercise
1.09 (0.98,1.22)
0.126
1.08 (0.96,1.22)
0.182
0.013
No
11,273
5663
50%
5610
50%
Yes
1339
643
48%
696
52%
Brainwave examination, sleep or wakefulness
1.60 (1.44,1.77)***
< 0.001
1.05 (0.91,1.21)
0.527
0.038
No
11,704
5864
50%
5840
50%
Yes
908
442
49%
466
51%
CFS chronic fatigue syndrome, CI confidence interval, SSRI selective serotonin reuptake inhibitor, SNRI serotonin and norepinephrine reuptake inhibitor, SARI serotonin antagonist and reuptake inhibitor, TCA tricyclic antidepressants, NDRI norepinephrine and dopamine reuptake inhibitor, NaSSA noradrenergic and specific serotonergic antidepressants, BZD benzodiazepine
*P < .05, **P < .01, ***P < .001
Fig. 2
Forest plot of conditional logical regression measured odds ratios and 95% confidence interval of chronic fatigue syndrome with different treatments. CFS chronic fatigue syndrome, CI confidence interval, SSRI selective serotonin reuptake inhibitor, SNRI serotonin and norepinephrine reuptake inhibitor, SARI serotonin antagonist and reuptake inhibitor, TCA tricyclic antidepressants, NDRI norepinephrine and dopamine reuptake inhibitor, NaSSA noradrenergic and specific serotonergic antidepressants, BZD benzodiazepine; *P < .0.05, **P < .0.01, ***P < .001
×
Table 3 and Fig. 3 presents the treatment received before the diagnosis of chronic fatigue syndrome with comorbidity sub-classification by having depression or anxiety disorder. The aORs of SARI usages and analgesic drug usages increased in both groups with depression and anxiety disorders. Among the participants with depression who received supportive individual psychotherapy, the aORs of risk of CFS was 1.85 (95% CI 1.02–3.35). As for the participants with anxiety disorder, the aORs of risk of CFS was 1.55 (95% CI 1.03–2.31) in those who also take muscle relaxants.
Table 3
Conditional logical regression measured odds ratios of chronic fatigue syndrome with different treatments stratified by depression or anxiety disorder
Variable
Control
CFS
Odds ratio
Multiple comparisons
Crude (95% CI)
p-value
Adjusted (95% CI)
p-value
p-value
Depression
No
Yes
No
Yes
SSRI
1.21 (0.95,1.54)
0.116
1.12 (0.87,1.45)
0.371
0.031
No
5656
202
5145
362
Yes
243
205
354
445
SNRI
1.38 (0.98,1.95)
0.065
1.24 (0.86,1.78)
0.253
0.021
No
5856
355
5438
671
Yes
43
52
61
136
SARI
2.04 (1.52,2.74)***
< 0.001
1.86 (1.36,2.56)***
< 0.001
< 0.001
No
5717
335
5071
561
Yes
182
72
428
246
TCAs
1.33 (0.78,2.26)
0.288
1.22 (0.70,2.14)
0.483
0.040
No
5840
387
5392
755
Yes
59
20
107
52
BZD
1.65 (0.88,3.11)
0.121
1.54 (0.78,3.04)
0.209
0.017
No
2310
18
1330
22
Yes
3589
389
4169
785
Muscle relaxant
1.73 (0.96,3.11)
0.07
1.34 (0.72,2.49)
0.351
0.029
No
5791
392
5289
757
Yes
108
15
210
50
Analgesic drug
3.61 (2.49,5.23)***
< 0.001
3.24 (2.18,4.82)***
< 0.001
< 0.001
No
1479
81
383
52
Yes
4420
326
5116
755
Supportive individual psychotherapy
1.68 (0.96,2.93)
0.069
1.85 (1.02,3.35)*
0.044
0.004
No
5603
390
5211
752
Yes
296
17
288
55
Re-educative individual psychotherapy
1.55 (0.88,2.72)
0.128
1.67 (0.91,3.04)
0.097
0.008
No
5632
390
5226
756
Yes
267
17
273
51
Stretching exercise
1.46 (0.89,2.39)
0.13
1.51 (0.90,2.53)
0.122
0.010
No
5525
384
5137
742
Yes
374
23
362
65
Therapeutic exercise
1.39 (0.94,2.04)
0.096
1.42 (0.95,2.12)
0.092
0.008
No
5296
367
4909
701
Yes
603
40
590
106
Brainwave examination, sleep or wakefulness
1.73 (0.63,4.72)
0.285
1.39
(0.48,3.99)
0.543
No
5781
402
5412
790
Yes
118
5
87
17
Anxiety disorder
No
Yes
No
Yes
SSRI
1.27 (1.06,1.51)**
0.009
1.08 (0.87,1.33)
0.486
0.041
No
5051
807
4003
1504
Yes
222
226
265
534
SNRI
1.40 (1.01,1.93)*
0.044
1.20 (0.84,1.72)
0.306
0.026
No
5231
980
4214
1895
Yes
42
53
54
143
SARI
1.80 (1.46,2.23)***
< 0.001
1.54 (1.23,1.94)***
< 0.001
< 0.001
No
5148
904
4011
1621
Yes
125
129
257
417
TCAs
1.26 (0.84,1.87)
0.264
1.10 (0.73,1.67)
0.639
0.053
No
5229
998
4195
1952
Yes
44
35
73
86
BZD
1.60 (1.12,2.28)**
0.009
1.45 (1.00,2.10)
0.051
0.004
No
2270
58
1279
73
Yes
3003
975
2989
1965
Muscle relaxant
1.71 (1.16,2.53)**
0.007
1.55 (1.03,2.31)*
0.034
0.003
No
5184
999
4120
1926
Yes
89
34
148
112
Analgesic drug
2.96 (2.26,3.87)***
< 0.001
2.76 (2.09,3.65)***
< 0.001
< 0.001
No
1422
138
334
101
Yes
3851
895
3934
1937
Supportive individual psychotherapy
0.95 (0.68,1.32)
0.749
0.98 (0.69,1.38)
0.892
0.074
No
5015
978
4028
1935
Yes
258
55
240
103
Re-educative individual psychotherapy
0.92 (0.65,1.30)
0.648
0.95 (0.66,1.36)
0.770
0.064
No
5041
981
4039
1943
Yes
232
52
229
95
Stretching exercise
0.97 (0.72,1.32)
0.867
0.99 (0.72,1.36)
0.961
0.080
No
4943
966
3970
1909
Yes
330
67
298
129
Therapeutic exercise
0.96 (0.76,1.23)
0.767
0.96 (0.75,1.23)
0.739
0.062
No
4740
923
3782
1828
Yes
533
110
486
210
Brainwave examination, sleep or wakefulness
0.64 (0.35,1.17)
0.144
0.67 (0.36,1.27)
0.221
0.018
No
5169
1014
4188
2014
Yes
104
19
80
24
CFS chronic fatigue syndrome, CI confidence interval, SSRI selective serotonin reuptake inhibitor, SNRI serotonin and norepinephrine reuptake inhibitor, SARI serotonin antagonist and reuptake inhibitor, TCA tricyclic antidepressants, BZD benzodiazepine
*P < .05, **P < .01, ***P < .001
Fig. 3
Forest plot of conditional logical regression measured odds ratios and 95% confidence interval of chronic fatigue syndrome with different treatments stratified by depression or anxiety disorder. CFS chronic fatigue syndrome, CI confidence interval, SSRI selective serotonin reuptake inhibitor, SNRI serotonin and norepinephrine reuptake inhibitor, SARI serotonin antagonist and reuptake inhibitor, TCA tricyclic antidepressants, BZD benzodiazepine; *P < 0.05, **P < .0.01., ***P < 0.001
×
As presented in Table 4 and Fig. 4, the analysis with sub-classification by age also demonstrates different patterns of medications used across different ages. BZD, muscle relaxants, and analgesic drug usages were indicated on increased aORs of risks of CFS in all the age groups. In contrast, the usages of SSRI, SARI, and TCA among participants aging from 35 to 64 years old had aORs of 1.24 (95% CI 1.04–1.47), 1.90 (95% CI 1.56–2.31), and 1.80 (95% CI 1.26–2.58), respectively. Among participants aging over 65 years old, the use of serotonin and norepinephrine reuptake inhibitor (SNRI) and SARI, with aORs being 2.15 (95% CI 1.22–3.81) and 1.93 (95% CI 1.46–2.57), respectively.
Table 4
Conditional logical regression measured odds ratios of chronic fatigue syndrome with different treatments stratified by age
Variable
Control
CFS
Odds ratio
Multiple comparisons
Crude (95% CI)
p-value
Adjusted (95% CI)
p-value
p-value
Age ≤ 34 y/o
No
Yes
No
Yes
SSRI
1.72 (1.26,2.35)***
< 0.001
1.01 (0.68,1.48)
0.977
0.075
No
4678
1180
4367
1140
Yes
380
68
686
113
SNRI
2.61 (1.34,5.11)**
0.005
1.37 (0.64,2.92)
0.413
0.032
No
4975
1236
4887
1222
Yes
83
12
166
31
SARI
3.03 (1.79,5.12)***
< 0.001
1.64 (0.92,2.92)
0.095
0.007
No
4823
1229
4435
1197
Yes
235
19
618
56
TCAs
3.21 (1.17,8.80)*
0.023
2.11 (0.68,6.49)
0.194
0.015
No
4984
1243
4910
1237
Yes
74
5
143
16
BZD
1.69 (1.44,1.98)***
< 0.001
1.37 (1.16,1.63)***
< 0.001
< 0.001
No
1625
703
809
543
Yes
3433
545
4244
710
NDRI
2.67 (0.71,10.07)
0.148
0.53 (0.09,2.98)
0.473
0.036
No
5029
1245
5002
1245
Yes
29
3
51
8
Muscle relaxant
3.61 (1.71,7.59)***
< 0.001
3.14 (1.45,6.79)**
0.004
< 0.001
No
4944
1239
4825
1221
Yes
114
9
228
32
Analgesic drug
2.37 (1.84,3.05)***
< 0.001
2.25 (1.73,2.92)***
< 0.001
< 0.001
No
1349
211
336
99
Yes
3709
1037
4717
1154
Supportive individual psychotherapy
0.97 (0.69,1.36)
0.843
0.97 (0.68,1.39)
0.884
0.068
No
4816
1177
4779
1184
Yes
242
71
274
69
Re-educative individual psychotherapy
1.03 (0.72,1.46)
0.875
1.04 (0.72,1.49)
0.849
0.065
No
4838
1184
4795
1187
Yes
220
64
258
66
Stretching exercise
0.92 (0.68,1.26)
0.615
0.93 (0.67,1.28)
0.659
0.051
No
4749
1160
4708
1171
Yes
309
88
345
82
Therapeutic exercise
0.82 (0.64,1.06)
0.133
0.83 (0.64,1.07)
0.152
0.012
No
4564
1099
4483
1127
Yes
494
149
570
126
Brainwave examination, sleep or wakefulness
0.80 (0.45,1.43)
0.454
0.80 (0.44,1.46)
0.473
0.036
No
4961
1222
4970
1232
Yes
97
26
83
21
Age 35–64 y/o
No
Yes
No
Yes
SSRI
1.97 (1.71,2.27)***
< 0.001
1.24 (1.04,1.47)*
0.016
0.001
No
1338
4520
1256
4251
Yes
133
315
215
584
SNRI
1.84 (1.39,2.44)***
< 0.001
1.08 (0.79,1.48)
0.619
0.048
No
1453
4758
1414
4695
Yes
18
77
57
140
SARI
2.93 (2.45,3.51)***
< 0.001
1.90 (1.56,2.31)***
< 0.001
< 0.001
No
1386
4666
1261
4371
Yes
85
169
210
464
TCAs
2.41 (1.71,3.38)***
< 0.001
1.80 (1.26,2.58)**
0.001
< 0.001
No
1440
4787
1426
4721
Yes
31
48
45
114
BZD
2.12 (1.94,2.31)***
< 0.001
1.57 (1.42,1.73)***
< 0.001
< 0.001
No
268
2060
97
1255
Yes
1203
2775
1374
3580
NDRI
1.93 (1.19,3.13)**
0.008
0.89 (0.52,1.51)
0.655
0.050
No
1464
4810
1460
4787
Yes
7
25
11
48
Muscle relaxant
2.09 (1.61,2.70)***
< 0.001
1.72 (1.31,2.25)***
< 0.001
< 0.001
No
1437
4746
1393
4653
Yes
34
89
78
182
Analgesic drug
3.62 (3.18,4.12)***
< 0.001
2.94 (2.57,3.37)***
< 0.001
< 0.001
No
523
1037
96
339
Yes
948
3798
1375
4496
Supportive individual psychotherapy
1.04 (0.87,1.25)
0.648
1.04 (0.86,1.26)
0.657
0.051
No
1406
4587
1386
4577
Yes
65
248
85
258
Re-educative individual psychotherapy
1.09 (0.91,1.32)
0.343
1.10 (0.90,1.33)
0.350
0.027
No
1411
4611
1391
4591
Yes
60
224
80
244
Stretching exercise
1.06 (0.90,1.24)
0.512
1.06 (0.90,1.26)
0.475
0.037
No
1384
4525
1370
4509
Yes
87
310
101
326
Therapeutic exercise
1.06 (0.93,1.20)
0.411
1.06 (0.92,1.21)
0.408
0.031
No
1332
4331
1304
4306
Yes
139
504
167
529
Brainwave examination, sleep or wakefulness
0.83 (0.62,1.12)
0.227
0.86 (0.63,1.17)
0.337
0.026
No
1445
4738
1448
4754
Yes
26
97
23
81
Age ≥ 65 y/o
No
Yes
No
Yes
SSRI
1.72 (1.37,2.17)***
< 0.001
1.13 (0.86,1.47)
0.379
0.029
No
4520
1338
4251
1256
Yes
315
133
584
215
SNRI
3.25 (1.91,5.55)***
< 0.001
2.15 (1.22,3.81)**
0.009
0.001
No
4758
1453
4695
1414
Yes
77
18
140
57
SARI
2.72 (2.09,3.53)***
< 0.001
1.93 (1.46,2.57)***
< 0.001
< 0.001
No
4666
1386
4371
1261
Yes
169
85
464
210
TCAs
1.47 (0.92,2.33)
0.106
0.99 (0.60,1.64)
0.981
< 0.001
No
4787
1440
4721
1426
Yes
48
31
114
45
BZD
3.16 (2.47,4.03)***
< 0.001
1.95 (1.5,2.54)***
< 0.001
< 0.001
No
2060
268
1255
97
Yes
2775
1203
3580
1374
NDRI
1.58 (0.61,4.08)
0.348
0.68 (0.24,1.95)
0.475
0.037
No
4810
1464
4787
1460
Yes
25
7
48
11
Muscle relaxant
2.37 (1.57,3.56)***
< 0.001
1.94 (1.26,2.98)**
0.003
< 0.001
No
4746
1437
4653
1393
Yes
89
34
182
78
Analgesic drug
7.90 (6.26,9.97)***
< 0.001
7.00 (5.43,9.04)***
< 0.001
< 0.001
No
1037
523
339
96
Yes
3798
948
4496
1375
Supportive individual psychotherapy
1.33 (0.95,1.85)
0.095
1.29 (0.90,1.83)
0.161
0.012
No
4587
1406
4577
1386
Yes
248
65
258
85
Re-educative individual psychotherapy
1.35 (0.96,1.91)
0.084
1.31 (0.91,1.89)
0.144
0.011
No
4611
1411
4591
1391
Yes
224
60
244
80
Stretching exercise
1.17 (0.87,1.58)
0.292
1.11 (0.81,1.52)
0.512
0.039
No
4525
1384
4509
1370
Yes
310
87
326
101
Therapeutic exercise
1.23 (0.97,1.56)
0.091
1.19 (0.92,1.53)
0.186
0.014
No
4331
1332
4306
1304
Yes
504
139
529
167
Brainwave examination, sleep or wakefulness
0.88 (0.50,1.55)
0.666
0.83 (0.46,1.52)
0.547
0.042
No
4738
1445
4754
1448
Yes
97
26
81
23
CFS chronic fatigue syndrome, CI confidence interval, SSRI selective serotonin reuptake inhibitor, SNRI serotonin and norepinephrine reuptake inhibitor, SARI serotonin antagonist and reuptake inhibitor, TCA tricyclic antidepressants, BZD benzodiazepine
*P < .05, **P < .01, ***P < .001
Fig. 4
Forest plot of conditional logical regression measured odds ratios and 95% confidence interval of chronic fatigue syndrome with different treatments stratified by age. CFS chronic fatigue syndrome, CI confidence interval, SSRI selective serotonin reuptake inhibitor, SNRI serotonin and norepinephrine reuptake inhibitor, SARI serotonin antagonist and reuptake inhibitor, TCA tricyclic antidepressants, BZD benzodiazepine; *P < .0.05, **P < .0.01, ***P < .0.001
×
In Table 5 and Fig. 5, we present the therapeutic options received by the patients with CFS and controls with sex specific sub-classification. In female patients, the adjusted odds ratio of risk of CFS were 1.22 (95% CI 1.01–1.48), 1.69 (95% CI 1.37–2.08), 1.72 (95% CI 1.17–2.53), 1.66 (95% CI 1.45–1.9), 1.56 (95% CI 1.16–2.1), 3.23 (95% CI 2.72–3.84), 1.36 (95% CI 1.08–1.72), 1.38 (95% CI 1.09–1.76), and 1.26 (95% CI 1.02–1.54), folds with SSRI use, SARI use, TCA use, BZD use, muscle relaxant use, analgesic drug use, supportive individual psychotherapy, re-educative psychotherapy, and stretching exercise. In male patients, the adjusted odds ratio risk of CFS were 1.92 (95% CI 1.19–3.08), 2.20 (95% CI 1.70–2.84), 1.55 (95% CI 1.36–1.76), 2.07 (95% CI 1.45–2.97), and 3.90 (95% CI 3.31–4.59) folds with SNRI use, SARI use, BZD use, muscle relaxant use, and analgesic drug use.
Table 5
Conditional logical regression measured odds ratios and 95% confidence interval of chronic fatigue syndrome with different treatments stratified by sex
Variable
Control
CFS
Odds ratio
multiple comparisons
Female
Crude (95% CI)
p-value
Adjusted (95% CI)
p-value
p-value
No
Yes
No
Yes
SSRI
1.95 (1.67,2.29)***
< 0.001
1.22 (1.01,1.48)*
0.035
0.003
No
2785
3073
2651
2856
Yes
182
266
316
483
SNRI
1.70 (1.25,2.31)***
< 0.001
1.00 (0.72,1.40)
0.982
0.076
No
2940
3271
2884
3225
Yes
27
68
83
114
SARI
2.57 (2.12,3.12)***
< 0.001
1.69 (1.37,2.08)***
< 0.001
< 0.001
No
2871
3181
2671
2961
Yes
96
158
296
378
TCAs
2.46 (1.7,3.55)***
< 0.001
1.72 (1.17,2.53)**
0.006
0.000
No
2929
3298
2907
3240
Yes
38
41
60
99
BZD
2.28 (2.03,2.56)***
< 0.001
1.66 (1.45,1.9)***
< 0.001
< 0.001
No
1288
1040
799
553
Yes
1679
2299
2168
2786
NDRI
1.80 (1.02,3.16)*
0.041
0.83 (0.45,1.53)
0.553
0.043
No
2954
3320
2942
3305
Yes
13
19
25
34
Muscle relaxant
1.98 (1.49,2.62)***
< 0.001
1.56 (1.16,2.10)**
0.004
0.000
No
2919
3264
2852
3194
Yes
48
75
115
145
Analgesic drug
4.12 (3.49,4.86)***
< 0.001
3.23 (2.72,3.84)***
< 0.001
< 0.001
No
860
700
233
202
Yes
2107
2639
2734
3137
Supportive individual psychotherapy
1.36 (1.09,1.70)**
0.006
1.36 (1.08,1.72)**
0.009
0.001
No
2797
3196
2816
3147
Yes
170
143
151
192
Re-educative individual psychotherapy
1.38 (1.10,1.74)**
0.006
1.38 (1.09,1.76)**
0.008
0.001
No
2815
3207
2823
3159
Yes
152
132
144
180
Stretching exercise
1.26 (1.04,1.54)*
0.02
1.26 (1.02,1.54)*
0.029
0.002
No
2763
3146
2780
3099
Yes
204
193
187
240
Therapeutic exercise
1.13 (0.97,1.32)
0.126
1.12 (0.95,1.32)
0.195
0.015
No
2649
3014
2634
2976
Yes
318
325
333
363
Brainwave examination, sleep or wakefulness
0.90 (0.62,1.30)
0.568
0.94 (0.64,1.39)
0.768
0.059
No
2903
3280
2916
3286
Yes
64
59
51
53
Male
No
Yes
No
Yes
SSRI
1.82 (1.51,2.21)***
< 0.001
1.18 (0.94,1.48)
0.165
0.013
No
3073
2785
2856
2651
Yes
266
182
483
316
SNRI
3.13 (2.02,4.85)***
< 0.001
1.92
(1.19,3.08)**
0.007
0.001
No
3271
2940
3225
2884
Yes
68
27
114
83
SARI
3.31 (2.62,4.20)***
< 0.001
2.20 (1.70,2.84)***
< 0.001
< 0.001
No
3181
2871
2961
2671
Yes
158
96
378
296
TCAs
1.59 (1.06,2.40)*
0.026
1.16 (0.75,1.80)
0.502
0.039
No
3298
2929
3240
2907
Yes
41
38
99
60
BZD
2.08 (1.87,2.32)***
< 0.001
1.55 (1.36,1.76)***
< 0.001
< 0.001
No
1040
1288
553
799
Yes
2299
1679
2786
2168
NDRI
1.93 (0.99,3.78)
0.055
0.84 (0.40,1.77)
0.640
0.049
No
3320
2954
3305
2942
Yes
19
13
34
25
Muscle relaxant
2.45 (1.74,3.45)***
< 0.001
2.07 (1.45,2.97)***
< 0.001
< 0.001
No
3264
2919
3194
2852
Yes
75
48
145
115
Analgesic drug
4.79 (4.10,5.59)***
< 0.001
3.90 (3.31,4.59)***
< 0.001
< 0.001
No
700
860
202
233
Yes
2639
2107
3137
2734
Supportive individual psychotherapy
0.88 (0.70,1.11)
0.276
0.86 (0.68,1.09)
0.225
0.017
No
3196
2797
3147
2816
Yes
143
170
192
151
Re-educative individual psychotherapy
0.94 (0.75,1.19)
0.633
0.92 (0.72,1.18)
0.527
0.041
No
3207
2815
3159
2823
Yes
132
152
180
144
Stretching exercise
0.91 (0.74,1.12)
0.374
0.89 (0.72,1.11)
0.306
0.024
No
3146
2763
3099
2780
Yes
193
204
240
187
Therapeutic exercise
1.05 (0.89,1.24)
0.533
1.05 (0.88,1.24)
0.592
0.046
No
3014
2649
2976
2634
Yes
325
318
363
333
Brainwave examination, sleep or wakefulness
0.79 (0.55,1.15)
0.222
0.77 (0.52,1.15)
0.201
0.015
No
3280
2903
3286
2916
Yes
59
64
53
51
CFS chronic fatigue syndrome, CI confidence interval, SSRI selective serotonin reuptake inhibitor, SNRI serotonin and norepinephrine reuptake inhibitor, SARI serotonin antagonist and reuptake inhibitor, TCA tricyclic antidepressants, BZD benzodiazepine
*P < .05, **P < .01, ***P < .001
Fig. 5
Forest plot of conditional logical regression measured odds ratios and 95% confidence interval of chronic fatigue syndrome with different treatments stratified by sex. CFS chronic fatigue syndrome, CI confidence interval, SSRI selective serotonin reuptake inhibitor, SNRI serotonin and norepinephrine reuptake inhibitor, SARI serotonin antagonist and reuptake inhibitor, TCA tricyclic antidepressants, BZD benzodiazepine; *P < .0.05, **P < .0.01, ***P < .0.001
×
Discussions
Our nationwide population-based study revealed that sampled patients with CFS experienced more comorbidities, such as depression and anxiety. These findings are consistent with those of previous studies. Furthermore, the treatments received by the participants before their diagnosis of CFS were also explored, and the results indicated that the use of specific types of antidepressants (e.g., SSRI, SARI, and TCA) was related to an increased risk of a subsequent diagnosis of CFS. In addition, a subgroup analysis also revealed that the treatment received differed by comorbidities, age, and sex.
Notably, no clear male or female predominance was observed in the present study. Other studies have reported that the prevalence of CFS among female individuals was approximately two-fold higher than that among male individuals [1, 4, 16]. However, several studies from East Asia, including Japan and China, have reported almost 1:1 sex ratios with respect to CFS prevalence [17, 18]. Different definitions of cases led to the variations in the prevalence and the incidence of CFS. We defined CFS using the CDC-1994 criteria in this study since it is the most common one that may resulted in recruit more cases [4, 19]. Cross-cultural differences in diagnostic practices for CFS and other conditions, especially neurasthenia, could explain the aforementioned differences in reported findings [20, 21], and this could ultimately lead to partly dissimilar populations being diagnosed. Another possible cause is the accessibility of the healthcare systems in Taiwan, as the National Health Insurance had covered over 99.9% of the civilians [22]. The increased accessibility could decrease the numbers of undetected cases. It therefore highlights the importance of the detection of male patients with CFS who might potentially be neglected.
Anzeige
The demographic data (Table 1) of the participants of the present study indicated higher comorbidity rates of depression, anxiety, inflammatory bowel diseases (IBD; Crohn’s disease and ulcerative colitis), autoimmune diseases, and metabolic disorders relative to the general population. Studies have reported an association between metabolic syndrome and CFS and identified altered fatty acid levels and lipid metabolism in individuals with CFS through further plasma metabolic profiling [23‐25]. Other studies have suggested the presence of a shared pathophysiological process in CFS, autoimmune rheumatic diseases, and inflammatory bowel diseases because of the reported associations among the conditions and their similar symptomatology [25‐28]. The role of the immune system in CFS could also be highlighted by our previous findings of the correlation between CFS and infectious diseases, indicating the involvement of post-infection dysregulated immune response [29, 30]. These findings highlight the complexity of CFS and its potential causes.
The greater prevalence of depression and anxiety disorder among individuals with CFS is an extensively studied topic. In both adult and adolescent populations, a high comorbidity of depression and anxiety has been reported in the literature [6, 31, 32]. Similarly, our analysis revealed an almost two times higher prevalence of depression and anxiety disorders in addition to insomnia among the participants diagnosed with CFS (Table 1). The causal relationship between CFS and concurrent psychiatric disorders remains unclear. Several neuroimaging studies have produced similar findings (including decreased cortical glutathione levels and altered resting-state functional connectivity in the anterior cingulate cortex) in both individuals with CFS and individuals with depression [33‐36], suggesting a shared pathophysiology.
The increased use of multiple types of antidepressants, especially SARI (mainly trazodone), has been observed before the diagnosis of CFS even after adjustments for clinical covariates, such as depression, anxiety, and insomnia (Tables 2 and 3.). In the diagnostic criteria for CFS, the applicable duration for defining unexplainable fatigue is a period in excess of 6 months [3], thus the prescription received by a patient at the point of diagnosis may correspond to the ongoing symptoms of CFS itself. Therefore, the medications prescribed during the aforementioned period may also provide us with a general overview of a patient’s status at the beginning of the clinical course of CFS.
In a clinical setting, trazodone is not only used as an antidepressant but also an efficacious treatment for insomnia at a low dose. Trazodone has been demonstrated to improve perceived sleep quality and reduce the number of early awakenings [37]. In Taiwan, trazodone is the fifth most frequently prescribed psychotropic drug in the outpatient clinics and has usually been used as a hypnotic [38]. In addition, it is also used off-label for anxiety and fibromyalgia in limited clinical settings [39]. SARI is speculated to be prescribed more frequently in such populations because of the accompanying subclinical symptoms of CFS, which include depression, anxiety, insomnia, and muscle pain [25]. This viewpoint is further supported by our finding regarding the increased pre diagnostic use of BZD, muscle relaxants, and analgesic drugs across all age groups in the participants with CFS (Table 4). Among the aforementioned symptoms, depression, and pain have been reported to be associated with decreased quality of life and physical functioning [40, 41]. Our data revealed that these disabling symptoms may occur in the early stage of the clinical course of CFS, and physicians must thus be aware of them.
Anzeige
With regard to sex, the pattern of antidepressant use differed between male and female participants with CFS. Before receiving a diagnosis of CFS, female participants were more likely to be taking SSRI and TCAs, whereas male participants were more likely to be taking SNRIs. This could be related to the sex-specific symptomatology in CFS, such as the higher prevalence of insomnia in female individuals relative to male individuals [42], which could lead to the prescription of sedative medications (e.g., TCAs and specific SSRIs) [43]. Higher ORs for receiving psychotherapy and rehabilitation were also observed in female individuals relative to male individuals, which could indicate a higher rate of engagement with medical services among female individuals with CFS and an insufficient awareness of CFS among male individuals. Similar sex differences have also been observed for other conditions, such as posttraumatic stress disorder and depression [44‐46].
It is noticeable that, in younger groups, an increased risk of CFS is mainly associated with the usage of muscle relaxants and analgesics, rather than anti-depressants (shown in Table 5 and Fig. 5). Muscle pain is a common symptom of CFS, and some researchers even describe that CFS is “old muscle in young body [47].” Furthermore, adolescents with CFS were indicated to have lower pain thresholds [48]. In the present study, CFS patients suffer from muscle pain symptoms more than control participants do, so the increased use of muscle relaxants and analgesics before diagnosis in CFS was noted. We further analyzed whether there was a gender difference in this group (age < 34y) and found that in younger females, the use of BZD and analgesics was related to subsequent CFS diagnosis (Additional file 2: Table S1 and Additional file 1: Figure S1). In males, in addition to BZD and analgesics, SNRI and muscle relaxants were also related to an increased risk of subsequent CFS. The phenomena suggest that compared to young females, young males have more diverse symptoms before CFS onset, leading to more varieties of medications being prescribed.
Our previous study analyzed both pharmacological and nonpharmacological treatments administered after the diagnosis of CFS. In contrast to the present study, we noted an increased use of antidepressants with dual-targeting mechanisms (serotonin– noradrenaline reuptake inhibitors and norepinephrine–dopamine reuptake inhibitors) after a diagnosis [49]. Such medications have relatively well-established effects on fatigue and pain under multiple conditions [50‐54]. As for nonpharmacological treatments, the number of patients receiving supportive psychotherapy, re-educative group psychotherapy, stretching exercise, and therapeutic exercise significantly increased after, but not before, diagnosis of CFS [49]. The contrast between these two studies indicates the extensive and multimodal approach taken in the Taiwanese health care system in treating CFS.
Studies have increasingly demonstrated the long-term postinfection symptoms of COVID-19, a phenomenon termed long COVID. The symptoms include persistent fatigue, pain, postexertional malaise, and appetite loss [55, 56]. Because the symptomatology of long COVID indicates certain similarities to that of CFS, a shared pathophysiology may be possible, such as alterations in oxidative stress or the hypothalamic–pituitary–adrenal (HPA) axis [57‐59]. Our results may also contribute to investigations into identifying populations that are at high risk of long COVID. One study showed that female sex is a risk factor for long COVID [55]. Another preliminary study focusing on patients with multiple sclerosis demonstrated that pre-existing depression and anxiety were associated with increased risk of long COVID [60]. These findings accord with our findings regarding CFS. The increased susceptibility to CFS and long COVID among these populations might be related to depression-related or anxiety-related increases in oxidative stress [61, 62] or HPA axis dysregulation [63, 64]. Because the research on this topic is limited, further studies should compare the mechanisms of CFS and long COVID and investigate the implications for prevention and treatment.
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This study has several limitations. First, the associations between CFS and the severity of depression and anxiety were not classified. Furthermore, due to the nature of the datasets from the NHIRD, the characteristics and the severity of the symptomatology in the patients were not recorded. The detailed associations between the medications prescribed and the severity of clinical symptoms couldn’t be investigated. As a results, the study aimed to speculate the corresponding symptomatology of the patients according to the genre of medications they received. Further prospective clinical studies focusing on the causal relationship and subgroup analysis were therefore warranted. Second, the present study could only examine a limited sample because the CDC-1994 diagnosis criteria for CFS (ICD-9-CM 780.71) were adopted for this study. These criteria mainly center on neurologic and neurocognitive symptoms; however, it did not incorporate other common accompanying symptoms, such as orthostatic intolerance, anorexia, and motor disturbance [65, 66], which are included in other newly proposed diagnostic criteria [19]. Therefore, the differences and similarities in the patterns of psychiatric comorbidities in CFS under different diagnostic criteria should be examined in future studies. Third, ethnic or geographic differences could not be clarified because the population examined in the present study mostly comprised East Asian individuals.
Conclusion
This study is the first nationwide population-based study to report a higher risk of CFS in patients with depression and anxiety disorder, especially those taking SSRIs, SARIs, and TCAs. In addition, BZD, muscle relaxants, and analgesic drugs were also revealed to be indicators of an elevated risk of CFS. These findings can increase the awareness of clinicians regarding high-risk populations and extend our current understanding of CFS.
Acknowledgements
We would like to extend acknowledgment to Dr. Jung-Nien Lai’s and Miss. Yu-Chi Yang's material support, and the listed institutes and Department of Medical Research at Mackay Memorial Hospital, and Mackay Medical College for funding support.
Declarations
Ethics approval and consent to participate
The authors assert that all procedures contributing to this work comply with the ethical standards of the relevant national and institutional committees on human experimentation and with the Helsinki Declaration of 1975, as revised in 2008. This study was approved by the Research Ethics Committee of the China Medical University Hospital (CMUH-104-REC2-115) and the Institutional Review Board of Mackay Memorial Hospital (16MMHIS074).
Consent for publication
The authors agree with the publication of this paper.
Competing interests
The authors declare that there is no competing interests regarding the publication of this paper.
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