Polyunsaturated fatty acids levels and initial presentation of somatic symptoms induced by interferon-alpha therapy in patients with
chronic hepatitis C viral infection
Jane Pei-Chen Chang1,2,5, Hsueh-Chou Lai2,6, Hui-Ting Yang3, Wen-Pang Su2,6, Cheng-
Yuan Peng2,6, Piotr Gałecki4, Anna Walczewska4, Carmine M. Pariante7, Kuan-Pin
Su,1,2,5,7*
1Graduate Institute of Neural and Cognitive Sciences, China Medical University, Taichung, TAIWAN
2School of Medicine, China Medical University, Taichung, TAIWAN
3Department of Nutrition, China Medical University, Taichung, TAIWAN
4Medical University of Łódź, Łódź, POLAND
5Department of Psychiatry & Mind-Body Interface Laboratory (MBI-Lab), China Medical University Hospital, Taichung, TAIWAN
6Department of Hepatogastroenterology, China Medical University Hospital, Taichung, TAIWAN
7Institute of Psychiatry, King’s College London, United Kingdom
*Address correspondence to:
Prof. Kuan-Pin Su
Department of Psychiatry, China Medical University Hospital,
No. 2, Yuh-Der Road, Taichung 404, Taiwan
Telephone number: 886-4-22062121 ext. 4126
Fax number: 886-4-22361230
E-mail: [email protected]
Conflicts of Interest: None
1
Acknowledgement
The work was supported by the following grants: MOST103-2320-B-039-MY3,
MOST103-2320-B-038-012-MY3, NSC 103-2923-B-039-002-MY3, 102-2911-I-039-
501, 101-2628-B-039-001-MY3 and 101-2320-B-038-020-MY2 from the Ministry of
Science and Technology and CMU103-S-03, DMR-103-078, 102-068 and 101-081
from the China Medical University in Taiwan.
2
Abstract
Objectives: Somatic symptoms are common in depressive disorder and are similar to
sickness behaviors due to inflammatory activation after cytokine administration.
Omega-3 polyunsaturated fatty acids (PUFAs) are natural anti-inflammatory agents
and may reduce inflammation-induced behavioral changes. The aim of this study was
to investigate the role of PUFAs on the development of somatic symptoms and
depression in patients of hepatitis C virus infection (HCV) receiving interferon-alpha
therapy (IFN-α) in a prospective manner.
Methods: In this 24-week, prospective cohort study, 43 patients with chronic HCV
ongoing IFN-αtherapy were assessed with the Mini-International Neuropsychiatric
Interview for major depressive episodes and Neurotoxicity Rating Scale (NRS) for
somatic symptoms.
Results: One-third later developed IFN-α-induced depression (DEP group). As
compared subjects without depression, DEP group had higher NRS scores (p<0.001),
lower eicosapentaenoic acid (EPA) levels (p=0.038) at week 2. Somatic symptoms,
regardless of painful/nonpainful characteristics, had positive association with
arachidonic acid (AA) (p<0.05), and negative association with EPA (p<0.05).
3
Conclusion: This study implies that early intervention with omega-3 PUFAs might be
a promising strategy to prevent depression and somatic symptoms in patients
receiving cytokine therapy.
Keywords: depression, painful symptoms, n-3, PUFAs, omega-3
4
Introduction
Depressive disorders with predominant somatic presentation, including general
weakness, malaise, fatigue, muscle and joint aches, loss of interest, poor appetite and
poor concentration, are the most common forms of depression.1-2 On the other hand,
somatic symptoms had been closely associated with immune/inflammatory system.3
Somatic symptoms has been described as the manifestation of activation of brain
cytokines system sensitization responding to immune reactions,4-6 which are similar to
inflammatory activation associated sickness behaviors of animals or humans after
receiving cytokine/prostaglandins E2 (PGE2) administration.5-6 The most supportive
evidence for the ‘inflammation theory’ of depression is that a therapeutic
administration of the interferon-alpha (IFN-α) induced depression, where in about a
third of patients with chronic hepatitis C viral infection (HCV) or cancers receiving
IFN-αdevelop depression.6-8
Previous genetic association and cross-sectional studies have demonstrated that
polyunsaturated fatty acids (PUFAs) may mediate in somatic symptoms in
depression.7 There are two main types of PUFAs: the omega-6 (n-6) series (cis-
linoleic acid [LA,18:2], γ-linolenic acid [GLA, 18:3, n-6], dihomo-GLA [20:3, n-6],
arachidonic acid [AA,20:4, n-6]); and the omega-3 (n-3) series (α-linolenic acid
[ALA, 18:3], eicosapentaenoic acid [EPA, 20:5, n-3], docosahexaenoic acid [DHA]).
Both n-3 and n-6 PUFAs are converted to eicosanoids for their biological functions
and are essential for survival of humans and other mammals.9 N-6 PUFAs becomes
the precursor of the pro-inflammatory arachidonic acid (AA), precursor of
prostaglandin (PGs) 2 series, thromboxanes (TXs) and Leukotrienes (LTs) 4 series.
5
Meanwhile, n-3 PUFAs forms the anti-inflammatory PGs 3 series and LTs 5 series. N-
3 PUFAs are critical in balancing immune function by reducing membrane n-6 PUFAs
and PGE2 synthesis and are associated with somatic manifestations in depression.10
Genetic variations on the key enzyme in PUFAs metabolism, the phospholipase A2
(PLA2), also have significant effect on somatic symptoms in both patients with IFN-
α-induced depression and the patients with major depression,7,11 possibly by affecting
the levels of n-3 PUFAs. In addition, a negative correlation between PUFAs levels and
somatization symptoms has also been reported in a cross-sectional study.12
The interpretation of previous cross-sectional case-controlled studies is limited by
possible confounders and weak cause-and-effect relationship. Therefore, the
prospective cohort of chronic HCV patients receiving IFN-αtherapy would provide an
excellent model to study the development of somatic symptoms in a prospective
human model. In this study, we aimed to investigate the roles of PUFAs on initial
somatic symptoms presentation induced by IFN-αtherapy in patients with chronic
HCV infection. We hypothesize that (1) the patients with HCV who later developed
depression during IFN-α treatment have higher levels of somatic symptoms at week 2,
(2) patients with HCV who later developed depression have higher levels of AA, and
(3) lower levels of EPA and DHA.
Methods
This was a 24-week, prospective cohort study. Eligible patients were adult patients
with chronic HCV, who were assessed by three hepatologists to be eligible for IFN-
αtherapy. Patients received combination therapy as their treatment for chronic HCV
for 24 weeks (1.5μg of peg-IFN-α-2beta per kilogram of body weight subcutaneously
6
once weekly, and 600-800 mg of ribavirin daily). Exclusion criteria included age over
70 years; any cause for liver disease other than HCV; any current psychiatric disorder
and current use of psychotropic agents. Patients were recruited from the Liver Center
of the China Medical University Hospital, Taichung, Taiwan by hepatologists and
referred to researchers to provide structured information about IFN-α-induced
neuropsychiatric adverse effects and depression, and the procedure of this study.
Patients had to fully understand and sign the informed consent before enrolment. The
study was approved by the China Medical University Hospital Institutional Review
Board.
Forty-three patients with chronic HCV were enrolled for weekly evaluation for
initial 2 weeks of IFN-αtherapy. At each assessment, patients were assessed with the
structured Mini-International Neuropsychiatric Interview (MINI) for confirmation of
diagnosis of major depressive episode and with self-reported Neurotoxicity Rating
Scale (NRS)13 for somatic and neuropsychiatric symptoms. Blood samples of 43
patients were available at baseline; however, only thirty-six participants were
available at week 2 of IFN-αtherapy for assesment of blood PUFAs level .
The NRS is a checklist questionnaire used for evaluation of cytokine therapy
related neuropsychiatric symptoms and is categorized into general symptoms, non-
painful somatic symptoms and painful somatic symptoms.13 With each item rated
from 0 to 10 on a visual analogue scale, the score ranges from 0-390. The general
symptoms include anxiety, health worries, sadness/depression, restlessness, no
interest in people, no interest in activities, difficulty making decisions, strange
thoughts, all-over sick feeling, distractibility, episodes of confusion, word-finding
7
problems, memory problems, irritability, decreased motivation, hallucinations, lack of
emotions, mood swings, tension, slowed movements, loss of interest in sex,
nightmares/dreams, and other unspecified symptoms; The non-painful somatic
symptoms include nausea, vomiting , tiredness/fatigue, tremors/shakiness, walking
problems, vision problems, bowel-bladder problems, fever, headache, difficulty getting
to sleep, difficulty staying asleep, sleeping too much, loss of appetite; The painful
symptoms include body aches, joint pain, other pain.
Fatty acid composition of erythrocyte membranes was analyzed and the level of
individual fatty acid was measured with gas chromatography of methyl esters (Lipid
Standards, FAME, Sigma Co., St. Louis, MO, USA). Fatty acid profiles were
identified by comparing the retention times with those of appropriate standard fatty
acid methyl esters. The phospholipids extracted from samples were dissolved in 1 ml
of 14% boron trifluoride methanol (BF3-methanol, SIGMA®), and 100ml of
heptadecanoic acid (Margaric acid, C17:0, SIGMA®) was added as internal standard,
then methylated reaction was performed by water bath heating at 100℃ for 30 min.
Finally, 2ml pentane and 1ml H2O were added and centrifuged for 10 min, took the
supernatant and redissolved in 100 l n-hexane then injected into gas chromatography
for fatty acid profile analysis.
The capillary gas chromatography (Trace GC, Thermo Finnigan) was equipped
with a 30m, 0.32mmid capillary column (cross-linked polyethylene glycol-TPA phase,
8
Sulpelco®) and frame ionized detector. The injector and detector temperatures were
230℃ and 270℃, respectively, and the split ratio was 100:1. Oven temperature was
set at 160℃ for 4 minutes at the initial stage, and was increased by 2.5℃/min to
225℃ then and held for 20 minutes. Peaks were recorded and interpreted by a
programmable integrator (Chromcard for Trace). Fatty acid profiles were identified
according to the retention time of appropriate standard fatty acid methyl esters.
Researchers who participated in the laboratory were blind to the information of coded
samples.
All statistical analysis was carried out with the Statistical Package for the Social
Science (SPSS), version 11.0 for windows. Demographic and clinical characteristics
of patients between depression (DEP) and non-depression (Non-DEP) groups were
compared by t-test or Chi-Square test where appropriate. Pearson correlation was used
to evaluate association between NRS scores and PUFAs levels, p value <0.05
indicates statistical significance.
Results
Fifteen out of 43 participants (34%) developed IFN-α-induced depression (DEP
group), and they had a significant higher second week NRS total scores (p < 0.001)
and greater increase in NRS total scores at the end of second week (p < 0.001) (Table
1). However, there were no differences between the DEP and Non-DEP groups in
terms of age and sex distribution, baseline NRS scores, blood PUFAs (AA, EPA,
9
DHA) levels at baseline and at week 2, and within 2-week changes of blood AA and
EPA levels. Moreover, after initiating IFN-α therapy, Non-DEP group had greater
drop in the changes of blood DHA level between week 2 to baseline when compared
to the DEP group (p = 0.031) (Table 1).
-----------------------------------------------
Insert Table 1 about Here
-----------------------------------------------
Correlation analysis further showed negative correlation between week 2 EPA
and NRS total, painful, and nonpainful symptom scores at weeks (p=0.032, 0.037, and
0.029, respectively; Table 2). We also found positive correlation between week 2
blood AA levels and NRS total, painful, and nonpainful symptom score changes
within week 1 (p=0.014, <0.001, =0.004, respectively; Table 3); and with painful
symptom scores at week 1 (p<0.005, Table 3). Furthermore, positive correlations was
found between within-2 week changes of AA blood levels and within-1 week painful
symptoms scores changes (p=0.036). However, no correlation was made between
NRS total, painful, non-painful symptoms scores and blood DHA levels (Data not
shown in the tables).
-----------------------------------------------
Insert Tables 2 & 3 about Here
-----------------------------------------------
10
Discussion
HCV patients receiving IFN-αtherapy who later developed depression (DEP
group) had significantly higher neurotoxicity symptom scores as early as the first two
weeks after initiating IFN-αtherapy in this prospective study. This is compatible with
our first hypothesis. Although IFN-α therapy may induce acute sickness behavior
manifestations similar to the presentation of depressive disorder,6 patients who later
developed IFN-α-induced depression tend to report a greater severity of the somatic
symptoms. Depressive disorders with predominantly somatic presentation are the
most common forms of depression.6 Moreover, previous reviews showed two of the
three most common symptoms (low mood: 76%, fatigue: 73%, sleep disturbances:
63%) reported during a current depressive episode were somatic.14 Hence, it is
important to note that the depressive symptoms of patients receiving IFN-α therapy
may be masked by the acute sickness behavioral symptoms at the beginning of the
treatment. Moreover, the manifestation of the somatic symptoms may be due to (1)
the inflammatory reactions induced by IFN-α via the induction of the nitric oxide
synthase (iNOS) and nitric oxide (NO) release and down-regulation of heme
oxygenase-1 (HO-1) expression,15 and (2) inflammatory and oxidative and nitrosative
reactions reported in patients with depression.16
Our study results echoes part of our second hypothesis in that DEP group had
lower EPA levels at week 2, but not in DHA or AA levels. Previous clinical trials and
meta-analyses have suggested that EPA, rather than DHA, might be the most active
component of omega-3 PUFAs’ antidepressant effects.17-21 Moreover, a 2-week,
double-blind, placebo-controlled trial comparing EPA, DHA, and placebo for the
11
prevention of IFN-α-induced depression showed that the incident rates of IFN-α-
induced depression were significantly lower in EPA-treated but not in DHA treated
patients (10% and 28%, respectively, versus 30% for placebo, p= 0.037).8 Genetic
variations of PLA2 and cyclooxygenase 2 (COX2) genes, the two key enzymes in the
metabolism of omega-3 PUFAs have also been associated with the development of
major depressive disorder and IFN-α-induced depression.7,22 PLA2 BanI GG or
COX2 rs4648308 AG genotypes have a higher risk of IFN-α-induced depression.7 In
addition, the at-risk PLA2 polymorphism is associated with lower EPA levels and the
at-risk COX2 polymorphism is associated with lower levels of both DHA and EPA
during IFN-α therapy.7
In this study, Non-DEP group also had a greater drop in blood DHA levels after
two weeks of IFN-αtherapy than DEP group. The initial drop in blood DHA level of
Non-DEP group may implicate that protective effect of releasing more free form
blood DHA to be available in non-depressed patients to counteract against depression.
IFN-α may activate PLA2 and decrease membrane DHA and increases free DHA.
Moreover, lower endogenous DHA had been identified as a risk factor for IFN-α-
induced depression in previous study;7 which further reflects less endogenous anti-
inflammatory capability in those who later develop depression.7 In addition, both
clinical 18 and cellular studies also supported the protective effect of DHA against
depression and associated somatic symptoms via modulation of the inflammatory
reactions, such as reducing expressions of tumor necrosis factor-α, IL-6, NOS, and
COX2, and inducing upregulation of HO-1.15
Omega-3 fatty acids modulation on inflammation had also been proposed as the
12
shared link between depression,23-24 cardiovascular diseases25 and associated somatic
symptoms.26 This study further supported role of PUFAs in depression associated
somatic symptoms by showing significant positive association between painful
symptom scores with blood AA levels and negative association with blood EPA levels
in HCV patients with IFN-α. Previous study showed inverse correlation between EPA
level and somatic symptoms,12 which further implicated that perception of somatic
complaints may be associated to EPA depletion changes. Moreover, EPA acts as the
precursor for eicosanoids and a modulator of cytokines.27 It has been proposed that
depression is accompanied by increased secretion of eicosanoids, such as
prostaglandins, and by an excessive secretion of proinflammatory cytokines.28 EPA
can act as the inhibitor of PLA2 to reduce the secretion of eicosanoids and
proinflammatory cytokines,29 which might have been associated with the
improvement of somatic symptoms in patients with depression.6 On the other hand,
the positive correlation between blood AA levels and painful somatic symptoms
maybe associated the actions of AA-derived-PGs. PGE2 and other pro-inflammatory
cytokines including interleukin IL-1 Beta and IL-6 tend to promote neuropathic pain
and hyperalgesia of sickness response via effects on central/peripheral neurons, glia
and endothelial cells.30
The balance between EPA, DHA, and AA are critical in the manifestation of
painful and non-painful somatic symptoms. Since EPA and DHA tend to suppress pro-
inflammatory activation of AA and reduce PGE2 synthesis, inactivate IL-1 beta-
induced PGE2 activation,31 attenuate IL-1-induced changes of nucleus accumbens
neurotransmitter release,32 and antagonize peripheral and neural production of
13
eicosanoids and cytokines, and improve neural plasticity induced by chronic pain.32
Moreover, Protein kinase C (PKC) is also activated in peripheral-pain neurons
following injury/inflammation, and mitogen-activated protein kinase (MAPK) has
been suggested to regulate central sensitization in inflammatory and neuropathic
pain.33 Meanwhile, n-3 PUFAs are able to inhibit PKC and MAPK actions in rats’
brain and interrupt painful pathway signaling.34 Hence, n-3 PUFAs may mediate in
depression-associated somatic symptoms via its anti-inflammatory actions in cellular
and molecular levels.
There are several limitations to this study. This sample size is relatively small;
hence generalization of the study results may be limited. Although blood samples of
43 patients were available at baseline; only thirty-six participants were available at
week 2 of IFN-αtherapy for assessment of blood PUFAs level. However, this study is
one of the first prospective study on the somatic symptoms presentation in patients
with IFN-α-induced depression. Secondly, although there were no differences
between DEP and Non-DEP group in terms of blood AA and DHA levels at week two,
which may be due to small sample size; there is a trend of greater DHA level in Non-
DEP group. Moreover, our study would be more comprehensive if we were to include
data in regards to the diets of the participants.
Conclusion
In conclusion, HCV patients receiving IFN-αtherapy who perceived higher
depressive and somatic symptoms as early as week 2 of IFN-αtherapy are prone
14
develop depression later during IFN-αtherapy. Contrariwise, those HCV patients with
higher basal DHA levels, possibly more free form DHA levels, receiving IFN-
αtherapy may be protected from cytokine induced depression.
N-3 PUFAs (EPA and DHA) associate with pain reduction in both
observational/clinical studies and are reported to participate in immune regulation via
balancing neuronal membrane stability, neurotransmission, and signal transduction;
and has been related to brain dysfunctions associated somatic symptoms of depression
and sickness behaviors. This prospective longitudinal study further showed painful
symptoms correlate positively with blood AA levels and negatively with blood EPA
levels in HCV patients with IFN-α-induced somatic symptoms, which further supports
the assumption that AA increase PGE2 and inflammation and contribute to sickness
behavior, while EPA antagonize AA activity by competing with AA as a substrate for
cyclo- and lipooxygenase and reduce of inflammatory metabolites (PGE2) production.
This study further suggests PUFAs levels and associated somatic symptoms may act
as potential predictors for IFN-α-induced depression as early as two weeks of
treatment.
15
Reference
1. Kent S, Bluthe RM, Kelley KW, Dantzer R. Sickness behavior as a new target
for drug development. Trends Pharmacol Sci 1992;13(1):24-28.
2. Konsman JP, Parnet P, Dantzer R. Cytokine-induced sickness behaviour:
mechanisms and implications. Trends Neurosci 2002;25(3):154-159.
3. Pariante CM. Chronic fatigue syndrome and the immune system: "findings in
search of meanings". Brain Behav Immun 2009;23(3):325-326.
4. Dantzer R. Somatization: a psychoneuroimmune perspective.
Psychoneuroendocrinology 2005;30(10):947-952.
5. Hart BL. Biological basis of the behavior of sick animals. Neurosci Biobehav
Rev1988;12(2):123-137.
6. Su KP. Biological mechanism of antidepressant effect of omega-3 fatty acids:
how does fish oil act as a 'mind-body interface'? Neurosignals.
2009;17(2):144-152.
7. Su KP, Huang SY, Peng CY, et al. Phospholipase A2 and cyclooxygenase 2
genes influence the risk of interferon-alpha-induced depression by regulating
polyunsaturated fatty acids levels. Biol Psychiatry 2010;67(6):550-557.
8. Su KP, Lai HC, Yang HT, et al. Omega-3 fatty acids in the prevention of
interferon-alpha-induced depression: results from a randomized, controlled
16
trial. Biol Psychiatry 2014;76(7):559-566.
9. Das UN. Essential fatty acids: biochemistry, physiology and pathology.
Biotechnol J 2006;1(4):420-439.
10. Su KP. Mind-body interface: the role of n-3 fatty acids in
psychoneuroimmunology, somatic presentation, and medical illness
comorbidity of depression. Asia Pac J Clin Nutr 2008;17 Suppl 1:151-157.
11. Pae CU, Yu HS, Kim JJ, et al. BanI polymorphism of the cytosolic
phospholipase A2 gene and mood disorders in the Korean population.
Neuropsychobiology 2004;49(4):185-188.
12. Riemer S, Maes M, Christophe A, Rief W. Lowered omega-3 PUFAs are
related to major depression, but not to somatization syndrome. J Affect Disord
2010;123(1-3):173-180.
13. Valentine AD, Meyers CA, Talpaz M. Treatment of neurotoxic side effects of
interferon-alpha with naltrexone. Cancer Invest 1995;13(6):561-566.
14. Tylee A. Low recognition of depression among outpatients by internists in
China. Evid Based Ment Health 2009;12(2):64.
15. Lu DY, Leung YM, Su KP. Interferon-alpha induces nitric oxide synthase
expression and haem oxygenase-1 down-regulation in microglia: implications
of cellular mechanism of IFN-alpha-induced depression. Int J
17
Neuropsychopharmacol 2013;16(2):433-444.
16. Talarowska M, Szemraj J, Galecki P. Myeloperoxidase gene expression and
cognitive functions in depression. Adv Med Sci 2015;60(1):1-5.
17. Lin PY, Huang SY, Su KP. A meta-analytic review of polyunsaturated fatty
acid compositions in patients with depression. Biol Psychiatry
2010;68(2):140-147.
18. Lin PY, Mischoulon D, Freeman MP, et al. Are omega-3 fatty acids
antidepressants or just mood-improving agents? The effect depends upon
diagnosis, supplement preparation, and severity of depression. Mol Psychiatry
2012;17(12):1161-1163; author reply 1163-1167.
19. Lin PY, Su KP. A meta-analytic review of double-blind, placebo-controlled
trials of antidepressant efficacy of omega-3 fatty acids. J Clin Psychiatry
2007;68(7):1056-1061.
20. Martins JG. EPA but not DHA appears to be responsible for the efficacy of
omega-3 long chain polyunsaturated fatty acid supplementation in depression:
evidence from a meta-analysis of randomized controlled trials. J Am Coll Nutr
2009;28(5):525-542.
21. Martins JG, Bentsen H, Puri BK. Eicosapentaenoic acid appears to be the key
omega-3 fatty acid component associated with efficacy in major depressive
18
disorder: a critique of Bloch and Hannestad and updated meta-analysis. Mol
Psychiatry 2012;17(12):1144-1149; discussion 1163-1147.
22. Bufalino C, Hepgul N, Aguglia E, Pariante CM. The role of immune genes in
the association between depression and inflammation: a review of recent
clinical studies. Brain Behav Immun 2013;31:31-47.
23. Su K-P. Inflammation in psychopathology of depression: Clinical, biological,
and therapeutic implications. BioMedicine 2012;2(2):68-74.
24. Su KP, Wang SM, Pae CU. Omega-3 polyunsaturated fatty acids for major
depressive disorder. Expert Opin Investig Drugs 2013;22(12):1519-1534.
25. Chang JP, Chang SS, Yang HT, Palani M, Chen CP, Su KP. Polyunsaturated
fatty acids (PUFAs) levels in patients with cardiovascular diseases (CVDs)
with and without depression. Brain Behav Immun 2015;44:28-31.
26. Chang JP, Chen YT, Su KP. Omega-3 Polyunsaturated Fatty Acids (n-3
PUFAs) in Cardiovascular Diseases (CVDs) and Depression: The Missing
Link? Cardiovasc Psychiatry Neurol 2009;2009:725310.
27. Fenton WS, Hibbeln J, Knable M. Essential fatty acids, lipid membrane
abnormalities, and the diagnosis and treatment of schizophrenia. Biol
Psychiatry 2000;47(1):8-21.
28. Maes M, Smith RS. Fatty acids, cytokines, and major depression. Biol
19
Psychiatry 1998;43(5):313-314.
29. Song C, Leonard BE, Horrobin DF. Dietary ethyl-eicosapentaenoic acid but
not soybean oil reverses central interleukin-1-induced changes in behavior,
corticosterone and immune response in rats. Stress 2004;7(1):43-54.
30. Watkins LR, Milligan ED, Maier SF. Glial activation: a driving force for
pathological pain. Trends Neurosci 2001;24(8):450-455.
31. Calder PC. Polyunsaturated fatty acids, inflammation, and immunity. Lipids
2001;36(9):1007-1024.
32. Song C. Omega-3, but not antidepressant sertraline, attenuates IL-1-induced
release of neurotransmitters in the nucleus accumbens: an in vivo
microdialysis study. Brain Behavior and Immun 2002;16(A):131.
33. Woolf CJ, Salter MW. Neuronal plasticity: increasing the gain in pain. Science
2000;288(5472):1765-1769.
34. Shapiro H. Could n-3 polyunsaturated fatty acids reduce pathological pain by
direct actions on the nervous system? Prostaglandins Leukot Essent Fatty
Acids 2003;68(3):219-224.
20
Table 1. Demographic data between depression and non-depression groups.
Non-DEP(N= 28)
Depression(N=15) p-Value
Female (%) 29% 47% 0.246
Age, yrs (mean +SD) 45.04+ 9.97 49.40+9.85 0.177
NRS (mean+SD)
Baseline (Week 0) 15.92+21.73 16.42+17.30 0.945
Week 2 23.81+20.31 63.36+ 27.23 <0.001**
Changes in 2 weeks 6.53+23.72 47.83+30.00 <0.001**
AA (mean+ SD)
Baseline (Week 0) 5.47+0.25 5.61+0.28 0.100
Week 2 5.35+0.18 5.37+0.20 0.694
Changes in 2 weeks -0.12+0.27 -0.23+0.40 0.269
EPA (mean+ SD )
Baseline (Week 0) 0.81+0.040 0.801+0.05 0.336
Week 2 0.79+0.048 0.76+0.04 0.038*
Changes in 2 weeks -0.02+ 0.050 -0.04+0.05 0.264
DHA (mean+ SD )
Baseline (Week 0) 3.40+0.40 3.25+0.1 0.147
Week 2 3.24+0.069 3.26+ 0.063 0.361
Changes in 2 weeks -0.160+ 0.38 0.02+0.11 0.031*
Note: AA, arachidonic acid; DHA, docosahexaenoic acid; EPA, eicosapentaenoic
acid; N, number; Non-DEP, non-depression group; NRS, sum of total neurotoxicity
rating scale scores; SD, standard deviation; yrs, years. *indicates statistical
significance of p<0.05 with Chi-Square; ** indicates statistical significance of p<0.01
with Chi-Square.
21
Table 2. The correlations between painful and non-painful somatic symptoms of
NRS and EPA level in HCV patients after 2 weeks of Interferon-alpha treatment.
EPA level Baseline Week 2¶ Changes in week 2¶
Pearson Correlation
R
Pearson Correlation
R
Pearson Correlation
RTotal NRS
Baseline (Week 0) 0.084 0.024 -0.045
Week 1 -0.130 -0.249 -0.138
Week 2 -0.071 -0.363* -0.312
Changes in 1 week -0.242 -0.238 -0.032
Changes in 2 weeks -0.139 -0.342 -0.232
Somatic scores
Baseline (Week 0) 0.035 0.010 -0.019
Week 1 -0.209 -0.222 -0.045
Week 2 -0.182 -0.354* -0.208
Changes in 1 week -0.281 -0.207 0.032
Changes in 2 weeks -0.212 -0.312 -0.139
Painful scores
Baseline (Week 0) -0.061 0.075 0.126
Week 1 -0.067 0.147 0.204
Week 2 -0.298 -0.369* -0.124
Changes in 1 week -0.101 0.105 0.191
Changes in 2 weeks -0.204 -0.313 -0.147
Note: EPA, eicosapentaenoic acid; HCV, hepatitis C viral infection; NRS, neurotoxicity rating scale; total NRS, sum of total neurotoxicity rating scale scores; Painful scores, sum of painful symptoms scores of NRS; R, The Pearson correlation coefficient; Somatic scores, refer to sum of non-painful symptoms scores of NRS. ¶Blood samples of 36 patients were available for measurements of EPA at 2nd week and changes in the 2 weeks.*Pearson correlation test was employed to determine the relationship between clinical variables.* indicates statistical significance of p<0.05.
22
Table 3. The correlations between painful and non-painful somatic symptoms of
NRS and AA level in HCV patients after 2 weeks of Interferon-alpha treatment.
AA Baseline Week 2¶Changes in 2 weeks¶
Pearson Correlation
R
Pearson Correlation
R
Pearson Correlation
RTotal NRS
Baseline (Week 0) -0.021 -0.310 -0.164
Week 1 0.061 0.284 0.111
Week 2 0.090 0.011 -0.071
Changes in 1 week 0.020 0.436* 0.231
Changes in 2 weeks 0.184 0.187 -0.055
Somatic scores
Baseline (Week 0) -0.030 -0.328 -0.167
Week 1 0.019 0.327 0.171
Week 2 -0.007 -0.028 -0.011
Changes in 1 week -0.007 0.506** 0.294
Changes in 2 weeks 0.086 0.191 0.035
Painful symptoms scores
Baseline (Week 0) -0.194 -0.219 0.040
Week 1 -0.031 0.465** 0.291
Week 2 -0.047 0.114 0.107
Changes in 1 week -0.004 0.658** 0.379*
Changes in 2 weeks 0.057 0.290 0.120
Note: AA, arachidonic acid; HCV, hepatitis C viral infection; NRS, neurotoxicity rating scale; total NRS, sum of total neurotoxicity rating scale scores; Painful scores, sum of painful symptoms scores of NRS; R, The Pearson correlation coefficient; Somatic scores, refer to sum of non-painful symptoms scores of NRS. ¶Blood samples of 36 patients were available for measurements of AA at 2nd week and changes in the 2 weeks.*Pearson correlation test was employed to determine the relationship between clinical variables.* indicates statistical significance of p<0.05; ** indicates statistical significance of p<0.01.
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