Changes in pain during a depressive episode and relationship to cytokine levels in Major Depressive Disorder

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A pathophysiological connection between depression and pain is still not revealed. Immunological activation has been found in both depression and pain. There are few studies of pain and immune activation in patients with depression, without inflammatory and autoimmune disorders Methods This is a naturalistic follow-up study of 50 patients with a major depressive disorder (MDD) depressive episode, without any inflammatory or autoimmune conditions. We have previously reported on the relationship between depression and cytokine levels. In this study we obtained data of depression, pain and cytokine levels before and after 12 weeks of depression treatment. All patients were medication-free at inclusion. Results At inclusion three out of four patients experienced pain, and the pain scores correlated with the depression scores. After treatment, as depression was relieved, the pain scores dropped significantly and were no longer correlated to the depression scores. There were no correlations between pain scores and cytokine levels. Pain level at inclusion did not correlate with depression treatment outcome. Conclusion Our findings indicate that pain is a feature of depression. Pain levels and cytokine values didn`t correlate. Pain at inclusion did not predict depression treatment outcome. Pain in depression cytokines follow-up study treatment outcome prediction Figures Figure 1 1. Introduction Depression is a disorder affecting how you feel, think and behave. It is the most common mental disorder and is distributed over several diagnoses [ 1 ]. According to the Diagnostic and Statistical Manual of Mental Disorders version 5 (DSM-5), the criteria for a depressive episode are sadness and/or loss of interest , in addition to several mental, cognitive and behavioral signs and symptoms. Although pain is not a symptom included in the diagnostic criteria of depression, the relation between depression and pain has been known for decades [ 2 – 4 ]. Pain is defined as "An unpleasant sensory and emotional experience associated with actual or potential tissue damage [ 5 ]. Pain is included as an item in the depression symptom severity scale, Inventory of Depressive Symptomatology (IDS) and numerous concepts have been developed to describe and explain the co-occurrence of depression and pain [ 6 ]. A multi-center study of 3568 out-clinic patients with a Major Depressive Disorder (MDD) and depressive episode found that almost 60% suffered from pain [ 7 ]. Data from the Netherlands Study of Depression and Anxiety (NESDA) showed that patients with pain were more prone to a chronic course of depression and anxiety disorders [ 8 ]. It has further been found that pain has a negative impact on depression treatment response [ 3 ], and that the severity of pain is a strong predictor of poor depression treatment outcome [ 9 ]. Research has also shown that there is a bidirectional influence of pain and depression. A change in severity of either symptom predicted subsequent severity of the other symptoms [ 10 ]. Pain is one of the five cardinal clinical signs of inflammation, and research on the pathophysiology of pain has provided insight into the involvement of cells and signaling molecules of the immune system [ 11 ]. Macrophages are immune cells resident in different tissues, or they may mature from circulating monocytes in the blood and migrate into the tissues and elicit tailored inflammatory tasks. Activated macrophages are dominant producers of cytokines, the signaling molecules of the innate immune system [ 12 ]. Experimental enhancement of macrophages in peritoneum of mice has been found to cause an increase in nociceptive pain response [ 13 ]. Furthermore, it has been shown that rats with a partial ligation of the sciatic nerve have enhanced pain sensitivity to thermal stimuli, and that depletion of macrophages reduce this effect [ 14 ]. A study by Morris and Esiri (1998) discovered expression of cytokines and the presence of their cellular receptors in normal human brain tissue [ 15 ]. The notion of cytokine activity in the brain is supported by the findings of resident immune cells in the central nervous tissue, the microglia [ 16 ], and that these cells express cytokines [ 17 ]. In addition there is evidence for the involvement of cytokines and glia in a "glial-cytokine-neuronal interactions", and that this is part of the underlying mechanism of persistent pain [ 18 ]. Immune system activation has also been found in depression. Meta-analyses have shown that depression is associated with elevated levels of IL-6, TNF [ 19 ] and the soluble cytokine receptor sIL-2R [ 20 ]. Previously we have found that a broader range of cytokines were elevated in a depressive episode and, normalized after recovery [ 21 ]. This suggests that cytokines play a central role in the pathophysiology of depression, and that different cytokines may contribute to different symptoms. Cytokines are thus molecules that are found to be associated with the biological mechanisms of both pain and depression. Although there is growing evidence showing that both pain and depression is related to immune abnormalities, there are few follow-up studies that have investigated the course and associations of depression, pain and cytokines in patients treated for a MDD depressive episode [ 22 ]. Here we investigate the prevalence of pain in a MDD depressive episode, how 12 weeks of treatment for the depressive episode is associated with a change in the prevalence of pain, and whether depression scores and pain are correlated at baseline and/or at follow-up. We also investigate whether pain at baseline is associated with treatment outcome in a MDD depressive episode, and finally, if cytokine levels are correlated with pain scores, or change in pain scores in MDD. 2. Methods 2.1 Study design This is a naturalistic observational follow-up study of depressed MDD patients without any inflammatory or autoimmune diseases. All patients were un-medicated at baseline. Depression symptom severity, pain scores and 13 cytokines were assessed before (baseline) and at follow up after 12 weeks of treatment for depression. We measured depression scores using the Inventory of Depressive Symptomatology (IDS) and the Montgomery Aasberg Depression Rating Scale (MADRS) at both time points. Using IDS to assess symptoms of depression, pain severity is included as item no. 25. We have earlier reported that the mean levels of various cytokines were elevated in the patient group at baseline and normalized after treatment [ 21 ]. In this paper we have studied the prevalence of pain in Major Depressive Disorder (MDD), in a depressive episode and after depression treatment. We have also examined the correlation between pain scores and cytokine levels in MDD. 2.2 Study population The study population was recruited from patients with ongoing depression who were referred to a psychiatric outpatient clinic. To be included, the patients had to fulfill the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV) criteria for MDD and have a score of at least 22 on the IDS scale. They had to be aged 18—60 years, and only drug-free patient were included. The minimum duration of the drug washout period was 3 weeks. This is in line with previous studies of cytokines in depression [ 19 , 23 – 25 ]. The majority of the patients had a much longer drug-free time period. Exclusion criteria were: presence of an autoimmune disorder, chronic inflammation, severe metabolic syndrome, body mass index (BMI; >34 kg/m2), psychotic disorder, alcohol or drug dependence, receiving anti-inflammatory, antiviral, antibiotic or immune modulating drugs, and inability to provide informed consent to participate. Patients with chronic inflammation were excluded by collecting information from the general practitioners, from interview with the patients, and from the hospital records. In addition, the patients’ C-reactive protein (CRP) values at baseline were used. A wide-screening blood analysis was used to reveal potential somatic comorbidity. This included liver enzymes, albumin, creatinine, glomerular filtration rate (calculated), alkaline phosphatase, blood lipids, hematologic status, erythrocyte sedimentation rate, CRP, ferritin, vitamin B12, methylmalonic acid, homocysteine, serum folate, thyroid status, cortisol, fasting blood glucoses, and glycated hemoglobin (HbA1c). We recruited 50 depressed MDD patients, 38 (76%) female and 12 (24%) male. The age at inclusion was 40.0 ± 12.0 years (mean ± SD) for the whole group (40.4 ± 12.8 years for females and 38.9 ± 9.7 years for males), and the BMI of this cohort was 25.8 ± 5.5 kg/m2. The data investigated in the present study are collected from the population in our earlier report of cytokine levels pre- and post-treatment in a MDD depressive episode compared to healthy controls [ 21 ]. At baseline all 50 patients fulfilled the DSM-IV criteria for a major depressive episode. The mean MADRS score was 27.8 (± 5.8), and the IDS was 37.1 (± 8.2). A total of 43 patients (86%) completed the 12 weeks of therapy. The MADRS was reduced to 13.4 (± 9.2), and IDS was reduced 18.6 (± 12.0). These are significant reductions with p < 0.001 for both. These data are presented in Table 1. 2.3 Treatment The choice of treatment was decided by the therapist and patients on an individual basis, according to the Norwegian National Guidelines for treatment of depression [ 26 ]. For mild depression, counseling and psychological intervention are the recommended interventions. Antidepressant medication should be considered when there is no response to non-pharmacological interventions. It should also be considered if the patient has had former moderate or severe depression. Also for moderate and severe depression, structured psychological treatment is recommended, but there is a stronger indication for the use of antidepressants. For severe depression, a combination of medication and structured psychological intervention is recommended. The guidelines underline the patient`s own choice and collaboration. 2.4 Pain assessment Pain was assessed with item 25 of IDS. This item assesses pain during the last week, and the severity is divided into four optional outcome scores. States there is no somatic complaints or pain. Complains of headaches, abdominal, back or joint pains that are intermittent and not disabling. Complains that the above pains are present most of the time. Functional impairment results from above pain. 2.5 Cytokine measurements A broad screening panel (human cytokine 27 plex, catalog no. 171A11127, Bio-Rad) was used to screen a selection of plasma samples (11 patients and 7 normal controls). Based on the screening and previous findings, a custom made 13 plex targeted against interleukin (IL)-1β, IL-1Ra, IL-2, IL-5, IL-6, IL-7, IL-8, IL-10, IL-15, granulocyte colony-stimulating factor (G-CSF), macrophage inflammatory protein 1 alpha (MIP-1α), tumor necrosis factor (TNF), and interferon gamma (IFN-γ) (Bio-Rad, Hercules, California, USA) was further used to determine the plasma targeted cytokine concentrations. All samples were thawed on ice, vortexed, and then spun down at 14 000 xg for 10 min at 4 o C prior to dilution (1:3), and fifty microliters was loaded onto plate. Individual sets of patient samples were loaded in duplicate on the same plate. The assays were optimized for low level detection with performing a tenfold dilution of the standards and extending incubations. All wash steps were performed using the Bio-Plex Pro™ Wash Station and the multiplex analysis were performed with a Luminex IS 100 (both from Bio-Rad, Hercules, CA, USA). An in-house spiked control was used to determine intra-assay and inter-assay percent of coefficient of variation (% CV). 2.6 Statistics To compare the pre- and post- treatment levels of the depression scores, a nonparametric two-paired-samples test (Wilcoxon test with repeated measures) was used. The same test was used for comparison of the pain scores pre-and post-treatment. The nonparametric Spearman`s correlations test was used for the correlation between pain and depression scores, and for the correlation between pain and the change in depression scores. This test was also used for the correlation between pain scores and cytokine levels. For the comparison of pain and IDS, the pain score was omitted from the IDS total score. 3 Results 3.1 Pain severity scores at baseline and after 12 weeks of treatment The median pain score at baseline (N = 50) was 1.54 (± 1.15) and was significantly reduced to 0.93 (± 0.91) at follow up (p < 0.001) These data are presented in Table 1. The pain scores at baseline were distributed as follows: twelve patients had a score of 0, thirteen had a score of 1, eleven had a score of 2, and fourteen had a score of 3. After 12 weeks of treatment (N = 43) seventeen patient scored 0, fourteen scored 1, ten scored 2 and only two scored 3. These data are rendered in Fig. 1. After 12 weeks of depression treatment (N = 43), 24 patients (55.8%) reported a lower pain score, 15 patients (34.9%) reported no change and 4 (9.3%) reported enhanced pain score. For the seven patients who dropped out, the pain scores at baseline were not significantly different from the other participants (Table 1). 3.2 Correlation between pain and depression At baseline the depression scores were correlated with pain scores. The Spearman correlation coefficient (r) for pain score and MADRS at baseline was 0.363 (p = 0.01), while for pain score and IDS it was 0.303 (p = 0.03). After 12 weeks of treatment, pain scores and depression scores were no longer significantly correlated, with r = 0.155 (p = 0.32) for MADRS and r = 0.235 (p = 0.13) for IDS. The change in pain scores from baseline until after 12 weeks (Δ pain) were not significantly correlated with the change in depression scores (Δ MADRS and Δ IDS). See Table 2. 3.3 Pain and depression treatment outcome The reduction in depression scores after 12 weeks of depression treatment was not significantly correlated to the pain level at baseline. For baseline, pain scores and the Δ MADRS the r was ÷ 0.067, with a p-value of 0.67. For baseline pain scores and the Δ IDS the r was ÷ 0.117 with a p-value of 0.45. The data are rendered in Table 2. We also compared change in MADRS and IDS from baseline till follow-up between those with low pain at baseline (score 0 and 1) and those with high pain at baseline (score 2 and 3). There was no difference between the two groups; the p-values were respectively 0.990 and 0.894. 3.4 Correlation between cytokines and pain There was no correlation between cytokine levels and pain scores, neither at baseline nor after 12 weeks. The change in pain scores (significant lower after 12 weeks of treatment), was not correlated to the cytokine levels, neither at baseline nor at follow-up. 3.5 Treatment without medication The choice of treatment was not an object of this study, and was decided by therapist and patients, as recommended in the Norwegian national treatment guidelines. Out of the 43 who completed the 12 weeks of treatment, 29 did not use any medication and 14 were treated with antidepressants. There were no significant differences between these groups for MADRS, IDS, and pain scores at baseline or follow up (data not shown). 4 Discussion Our main finding is that as many as three out of four depressed MDD patients experienced pain, and there was a significant drop in pain scores after 12 weeks of treatment as depression was relieved. We did not find that pain was associated with treatment effect, nor with cytokine levels. Our finding of a high occurrence of pain in depression is in line with former findings [ 7 , 27 – 29 ]. We also found that pain scores were correlated to depression severity before treatment, and that both depression and pain scores were significantly reduced after 12 weeks of depression treatment. However, the scores were no longer correlated after ended treatment. Altogether our findings indicate that pain is a feature of a MDD depressive episode. This may have an important clinical implication. In the RESPECT trial Kroenke and co-workers showed that “recognizing and optimizing the management of comorbid pain that commonly coexists with depression may be important in enhancing depression response and remission rates” [ 29 ]. We found that neither pain score at baseline nor change in pain score after treatment was correlated to depression treatment outcome. Further, no difference in depression treatment outcome between those with high and low pain scores at baseline was found. This indicates that pain does not seem to predict depression treatment outcome. These findings contrast with other findings [ 3 , 9 ]. Cytokines have been found to be involved in a "glial-cytokine-neuronal interaction", the underlying mechanism of persistent pain [ 18 ]. We have earlier shown that the levels of various cytokines are elevated in a MDD depressive episode and normalized after recovery [ 21 ]. In this present study we found indications for pain being a feature of depression. On the other hand, we found no correlations between cytokine levels and pain scores, neither at baseline nor after treatment. Further, cytokine levels were not correlated to the change in pain scores. Thus, we were not able to provide evidence for a possible causal relation between depression, cytokines and pain. There is a need for more research into the relation between cytokines and pain in depression. In a recent paper the support for a Psycho-Neuro-Endocrine-Immune basis for a placebo mediated analgesia and anxiolytic response is reviewed [ 30 ]. 5 Limitations One possible limitation of the present study might be that we assessed cytokines in peripheral blood, and pain is constituted of mechanisms both in the periphery and in the central nervous system. However, there are findings indicating a connection between peripherally assessed cytokines and cytokine activity in the brain. Former studies have shown that the blood brain barrier (BBB) is impeded by immune activation [ 20 ], and there is evidence of a strong correlation between plasma and CSF levels of certain cytokines [ 31 , 32 ]. Cytokines produced and assessed elsewhere in the body are able to bind to receptors on brain immune cells, such as microglia, and further induce the expression of cytokines[ 33 , 34 ]. In addition, an increase in serum cytokine levels have also been observed after non-neurological surgery that was accompanied by even higher cytokine levels in the cerebrospinal fluid (CSF) [ 35 ]. Another possible limitation is the relatively small number of individuals (N = 50), making the study vulnerable to type II error. A further limitation may be that the patients were enrolled from a population referred with MDD to a specialized psychiatric outpatient clinic, making these results less relevant to other depressed patients. One strength of this study is that the patients were thoroughly screened for inflammatory and immunological diseases. Further, the patients were all free of medication at inclusion. This rules out the potential influence from other conditions and medication on the experienced pain and cytokine levels at baseline. Declarations Ethics approval and consent to participate : The study was approved by the local Ethics Committee: Regional komite ́ for medisinsk og helsefaglig forskningsetikk Sør-Øst C (REK Sør-Øst C), Postboks 1130 Blindern, NO-1130 Oslo, Norway . The patients provided written consent to participate after receiving verbal and written information regarding the study. All methods were performed in accordance with the relevant guidelines and regulations. Availability of data and material : The dataset generated during and analyzed during the current study are not publicly available du to requirements from Regional Ethics Committee but are available from the corresponding author on reasonable request. Funding : The study is fully funded by Ringerike Psychiatric Center and Vestre Viken Hospital Trust, Norway. Acknowledgements : The authors would like to thank Vestre Viken Hospital Trust and Ringerike Psychiatric Center for funding the study. We would also like to thank the South-Eastern Norway Regional Health Authority’s (HSØ) Norwegian research network on mood disorders (NORMOOD) for initiating the study, and Tove Hæreid Otterstad for her coordination of the NORMOOD project. Further, we are indebted to Anne Skjerstein for taking care of the blood samples and the logistics. Finally, we will express our gratitude to the patients that participated in the study. Consent for publication : Not applicable. Competing interests : The authors declare no conflict of interest. Authors ̓ contributions : JD, OAA, HO and UFM designed the study. JD and HCDA participated in data collection. JD analyzed the data. JD wrote the first draft of the manuscript. All co-authors interpreted the data, participated in revising the manuscript and approved the final version. References Kessler, R.C. and E.J. Bromet, The epidemiology of depression across cultures . Annu Rev Public Health, 2013. 34 : p. 119–38. Dworkin, S.F. and L. LeResche, Research diagnostic criteria for temporomandibular disorders: review, criteria, examinations and specifications, critique . J Craniomandib Disord, 1992. 6 (4): p. 301–55. Fishbain, D.A., et al., Does pain interfere with antidepressant depression treatment response and remission in patients with depression and pain? An evidence-based structured review . Pain Med, 2014. 15 (9): p. 1522–39. Romano, J.M. and J.A. 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Bromander, S., et al., Changes in serum and cerebrospinal fluid cytokines in response to non-neurological surgery: an observational study . J Neuroinflammation, 2012. 9 : p. 242. Tables Table 1. Symptom scores of depression and pain, pre- and post- treatment Variable Week 0 Week 12 p IDS 37.1 (±8.2) 18.6 (±12.0) <0.001 MADRS 27.8 (±5.8) 13.4 (±9.2) <0.001 Pain score 1.54 (±1.15) 0.93 (±0.93) <0.001 IDS= Inventory of Depressive Symptomatology MADRS= Montgomery Aasberg Depression Rating Scale Table 2. Correlations Correlation between: Spearman`s rho p- value Baseline pain and Δ MADRS ÷ 0.067 0.67 Baseline pain and Δ IDS ÷0.117 0.45 Δ pain and Δ MADRS 0.460 0.77 Δ pain and Δ IDS 0.137 0.38 Week 0 Week 12 Spearman`s rho p- value Spearman`s rho p- value pain and MADRS 0.363 0.01 0.155 0.32 pain and IDS 0.303 0.03 0.235 0.13 Δ = Change from baseline till follow-up MADRS = Montgomery Aasberg Depression Rating Scale IDS = Inventory of Depressive Symptomatology Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 22 Jan, 2024 Read the published version in Nordic Journal of Psychiatry → Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-1659294","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":108094102,"identity":"cdf3052a-f05a-4717-8389-aa2a53e09e89","order_by":0,"name":"Johan Dahl","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA9UlEQVRIiWNgGAWjYBACxgYeEMXMYMDOfICBgQ3IlgAjYrQwsyUQp4WBAa6Fx4A4LcztvQc/FzBYy5sz83zd8KHscDSDdPPDG4w7bHA7rOdcsvQMhnTDnc28227OOHc4t0HmmLEF45k03Fpm5BhI8zAcZtxwmHfbbd62w7n7bySYSTC2Hcanxfg3UIv9hsM8z8BaGiTSvxHSYgayJRGohQ2qJYeALT1nzKx5DNKTNxxmMwP6JR3olzPFFoltuP1i2N5jfJunwtp2w/HmZzc+lFnnNki3b7zxsQ13iBk2gEgDdOEEnBoYGOTxyI2CUTAKRsEogAAAmSNTwjgMEeUAAAAASUVORK5CYII=","orcid":"","institution":"Modum Bad Research Institute","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Johan","middleName":"","lastName":"Dahl","suffix":""},{"id":108094103,"identity":"087e1578-5290-460d-b002-165abda809b1","order_by":1,"name":"Heidi Ormstad","email":"","orcid":"","institution":"University of South-Eastern Norway","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Heidi","middleName":"","lastName":"Ormstad","suffix":""},{"id":108094104,"identity":"133bd501-3ff0-4392-acc1-920e0a378eaf","order_by":2,"name":"Hans Christian Dalsbotten Aass","email":"","orcid":"","institution":"Oslo University Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Hans","middleName":"Christian Dalsbotten","lastName":"Aass","suffix":""},{"id":108094107,"identity":"3549a663-d923-4997-a6e8-94dedfc060b8","order_by":3,"name":"Ulrik Fredrik Malt","email":"","orcid":"","institution":"University of Oslo","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Ulrik","middleName":"Fredrik","lastName":"Malt","suffix":""},{"id":108094109,"identity":"21f8d309-c019-4c20-8d6e-a92fea98cace","order_by":4,"name":"Ole A. Andreassen de","email":"","orcid":"","institution":"University of Oslo","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Ole","middleName":"A. Andreassen","lastName":"de","suffix":""}],"badges":[],"createdAt":"2022-05-15 21:29:02","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-1659294/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-1659294/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1080/08039488.2023.2290654","type":"published","date":"2024-01-22T23:05:46+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":21835760,"identity":"aba64515-97e9-40a1-a73b-5d771f779ea6","added_by":"auto","created_at":"2022-05-24 16:30:32","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":4676,"visible":true,"origin":"","legend":"\u003cp\u003ePain scores week 0 (N=50) week 12 (N=43) and in the drop-out group (N=7)\u003c/p\u003e","description":"","filename":"Onlinedrawingimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-1659294/v1/d0c6f9efd5b476deaef6db60.png"},{"id":53893436,"identity":"175f4933-2e9b-4a00-a52e-d385abcc4a34","added_by":"auto","created_at":"2024-04-01 23:05:55","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":354094,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-1659294/v1/7fd48911-c8e5-4653-9684-0aead29c90c4.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Changes in pain during a depressive episode and relationship to cytokine levels in Major Depressive Disorder","fulltext":[{"header":"1. Introduction","content":"\u003cp\u003eDepression is a disorder affecting how you feel, think and behave. It is the most common mental disorder and is distributed over several diagnoses [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. According to the Diagnostic and Statistical Manual of Mental Disorders version 5 (DSM-5), the criteria for a depressive episode are \u003cem\u003esadness\u003c/em\u003e and/or \u003cem\u003eloss of interest\u003c/em\u003e, in addition to several mental, cognitive and behavioral signs and symptoms. Although pain is not a symptom included in the diagnostic criteria of depression, the relation between depression and pain has been known for decades [\u003cspan additionalcitationids=\"CR3\" citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Pain is defined as \"An unpleasant sensory and emotional experience associated with actual or potential tissue damage [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Pain is included as an item in the depression symptom severity scale, Inventory of Depressive Symptomatology (IDS) and numerous concepts have been developed to describe and explain the co-occurrence of depression and pain [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eA multi-center study of 3568 out-clinic patients with a Major Depressive Disorder (MDD) and depressive episode found that almost 60% suffered from pain [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Data from the Netherlands Study of Depression and Anxiety (NESDA) showed that patients with pain were more prone to a chronic course of depression and anxiety disorders [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. It has further been found that pain has a negative impact on depression treatment response [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e], and that the severity of pain is a strong predictor of poor depression treatment outcome [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Research has also shown that there is a bidirectional influence of pain and depression. A change in severity of either symptom predicted subsequent severity of the other symptoms [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e].\u003c/p\u003e \u003cp\u003ePain is one of the five cardinal clinical signs of inflammation, and research on the pathophysiology of pain has provided insight into the involvement of cells and signaling molecules of the immune system [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Macrophages are immune cells resident in different tissues, or they may mature from circulating monocytes in the blood and migrate into the tissues and elicit tailored inflammatory tasks. Activated macrophages are dominant producers of cytokines, the signaling molecules of the innate immune system [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Experimental enhancement of macrophages in peritoneum of mice has been found to cause an increase in nociceptive pain response [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Furthermore, it has been shown that rats with a partial ligation of the sciatic nerve have enhanced pain sensitivity to thermal stimuli, and that depletion of macrophages reduce this effect [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. A study by Morris and Esiri (1998) discovered expression of cytokines and the presence of their cellular receptors in normal human brain tissue [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. The notion of cytokine activity in the brain is supported by the findings of resident immune cells in the central nervous tissue, the microglia [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e], and that these cells express cytokines [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. In addition there is evidence for the involvement of cytokines and glia in a \"glial-cytokine-neuronal interactions\", and that this is part of the underlying mechanism of persistent pain [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eImmune system activation has also been found in depression. Meta-analyses have shown that depression is associated with elevated levels of IL-6, TNF [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e] and the soluble cytokine receptor sIL-2R [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Previously we have found that a broader range of cytokines were elevated in a depressive episode and, normalized after recovery [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. This suggests that cytokines play a central role in the pathophysiology of depression, and that different cytokines may contribute to different symptoms. Cytokines are thus molecules that are found to be associated with the biological mechanisms of both pain and depression.\u003c/p\u003e \u003cp\u003eAlthough there is growing evidence showing that both pain and depression is related to immune abnormalities, there are few follow-up studies that have investigated the course and associations of depression, pain and cytokines in patients treated for a MDD depressive episode [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eHere we investigate the prevalence of pain in a MDD depressive episode, how 12 weeks of treatment for the depressive episode is associated with a change in the prevalence of pain, and whether depression scores and pain are correlated at baseline and/or at follow-up. We also investigate whether pain at baseline is associated with treatment outcome in a MDD depressive episode, and finally, if cytokine levels are correlated with pain scores, or change in pain scores in MDD.\u003c/p\u003e"},{"header":"2. Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003e2.1 Study design\u003c/h2\u003e \u003cp\u003eThis is a naturalistic observational follow-up study of depressed MDD patients without any inflammatory or autoimmune diseases. All patients were un-medicated at baseline. Depression symptom severity, pain scores and 13 cytokines were assessed before (baseline) and at follow up after 12 weeks of treatment for depression. We measured depression scores using the Inventory of Depressive Symptomatology (IDS) and the Montgomery Aasberg Depression Rating Scale (MADRS) at both time points. Using IDS to assess symptoms of depression, pain severity is included as item no. 25. We have earlier reported that the mean levels of various cytokines were elevated in the patient group at baseline and normalized after treatment [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. In this paper we have studied the prevalence of pain in Major Depressive Disorder (MDD), in a depressive episode and after depression treatment. We have also examined the correlation between pain scores and cytokine levels in MDD.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003e2.2 Study population\u003c/h2\u003e \u003cp\u003eThe study population was recruited from patients with ongoing depression who were referred to a psychiatric outpatient clinic. To be included, the patients had to fulfill the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV) criteria for MDD and have a score of at least 22 on the IDS scale. They had to be aged 18\u0026mdash;60 years, and only drug-free patient were included. The minimum duration of the drug washout period was 3 weeks. This is in line with previous studies of cytokines in depression [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan additionalcitationids=\"CR24\" citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. The majority of the patients had a much longer drug-free time period. Exclusion criteria were: presence of an autoimmune disorder, chronic inflammation, severe metabolic syndrome, body mass index (BMI; \u0026gt;34 kg/m2), psychotic disorder, alcohol or drug dependence, receiving anti-inflammatory, antiviral, antibiotic or immune modulating drugs, and inability to provide informed consent to participate. Patients with chronic inflammation were excluded by collecting information from the general practitioners, from interview with the patients, and from the hospital records. In addition, the patients\u0026rsquo; C-reactive protein (CRP) values at baseline were used. A wide-screening blood analysis was used to reveal potential somatic comorbidity. This included liver enzymes, albumin, creatinine, glomerular filtration rate (calculated), alkaline phosphatase, blood lipids, hematologic status, erythrocyte sedimentation rate, CRP, ferritin, vitamin B12, methylmalonic acid, homocysteine, serum folate, thyroid status, cortisol, fasting blood glucoses, and glycated hemoglobin (HbA1c).\u003c/p\u003e \u003cp\u003eWe recruited 50 depressed MDD patients, 38 (76%) female and 12 (24%) male. The age at inclusion was 40.0\u0026thinsp;\u0026plusmn;\u0026thinsp;12.0 years (mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD) for the whole group (40.4\u0026thinsp;\u0026plusmn;\u0026thinsp;12.8 years for females and 38.9\u0026thinsp;\u0026plusmn;\u0026thinsp;9.7 years for males), and the BMI of this cohort was 25.8\u0026thinsp;\u0026plusmn;\u0026thinsp;5.5 kg/m2. The data investigated in the present study are collected from the population in our earlier report of cytokine levels pre- and post-treatment in a MDD depressive episode compared to healthy controls [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eAt baseline all 50 patients fulfilled the DSM-IV criteria for a major depressive episode. The mean MADRS score was 27.8 (\u0026plusmn;\u0026thinsp;5.8), and the IDS was 37.1 (\u0026plusmn;\u0026thinsp;8.2). A total of 43 patients (86%) completed the 12 weeks of therapy. The MADRS was reduced to 13.4 (\u0026plusmn;\u0026thinsp;9.2), and IDS was reduced 18.6 (\u0026plusmn;\u0026thinsp;12.0). These are significant reductions with p\u0026thinsp;\u0026lt;\u0026thinsp;0.001 for both. These data are presented in Table\u0026nbsp;1.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003e2.3 Treatment\u003c/h2\u003e \u003cp\u003eThe choice of treatment was decided by the therapist and patients on an individual basis, according to the \u003cem\u003eNorwegian National Guidelines for treatment of depression\u003c/em\u003e [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. For mild depression, counseling and psychological intervention are the recommended interventions. Antidepressant medication should be considered when there is no response to non-pharmacological interventions. It should also be considered if the patient has had former moderate or severe depression. Also for moderate and severe depression, structured psychological treatment is recommended, but there is a stronger indication for the use of antidepressants. For severe depression, a combination of medication and structured psychological intervention is recommended. The guidelines underline the patient`s own choice and collaboration.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003e2.4 Pain assessment\u003c/h2\u003e \u003cp\u003ePain was assessed with item 25 of IDS. This item assesses pain during the last week, and the severity is divided into four optional outcome scores.\u003c/p\u003e \u003cp\u003e \u003col\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eStates there is no somatic complaints or pain.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eComplains of headaches, abdominal, back or joint pains that are intermittent and not disabling.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eComplains that the above pains are present most of the time.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eFunctional impairment results from above pain.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003c/ol\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003e2.5 Cytokine measurements\u003c/h2\u003e \u003cp\u003eA broad screening panel (human cytokine 27 plex, catalog no. 171A11127, Bio-Rad) was used to screen a selection of plasma samples (11 patients and 7 normal controls). Based on the screening and previous findings, a custom made 13 plex targeted against interleukin (IL)-1β, IL-1Ra, IL-2, IL-5, IL-6, IL-7, IL-8, IL-10, IL-15, granulocyte colony-stimulating factor (G-CSF), macrophage inflammatory protein 1 alpha (MIP-1α), tumor necrosis factor (TNF), and interferon gamma (IFN-γ) (Bio-Rad, Hercules, California, USA) was further used to determine the plasma targeted cytokine concentrations. All samples were thawed on ice, vortexed, and then spun down at 14 000 xg for 10 min at 4 \u003csup\u003eo\u003c/sup\u003eC prior to dilution (1:3), and fifty microliters was loaded onto plate. Individual sets of patient samples were loaded in duplicate on the same plate. The assays were optimized for low level detection with performing a tenfold dilution of the standards and extending incubations. All wash steps were performed using the Bio-Plex Pro\u0026trade; Wash Station and the multiplex analysis were performed with a Luminex IS 100 (both from Bio-Rad, Hercules, CA, USA). An in-house spiked control was used to determine intra-assay and inter-assay percent of coefficient of variation (% CV).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003e2.6 Statistics\u003c/h2\u003e \u003cp\u003eTo compare the pre- and post- treatment levels of the depression scores, a nonparametric two-paired-samples test (Wilcoxon test with repeated measures) was used. The same test was used for comparison of the pain scores pre-and post-treatment. The nonparametric Spearman`s correlations test was used for the correlation between pain and depression scores, and for the correlation between pain and the change in depression scores. This test was also used for the correlation between pain scores and cytokine levels. For the comparison of pain and IDS, the pain score was omitted from the IDS total score.\u003c/p\u003e \u003c/div\u003e"},{"header":"3 Results","content":"\u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003e3.1 Pain severity scores at baseline and after 12 weeks of treatment\u003c/h2\u003e \u003cp\u003eThe median pain score at baseline (N\u0026thinsp;=\u0026thinsp;50) was 1.54 (\u0026plusmn;\u0026thinsp;1.15) and was significantly reduced to 0.93 (\u0026plusmn;\u0026thinsp;0.91) at follow up (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) These data are presented in Table\u0026nbsp;1. The pain scores at baseline were distributed as follows: twelve patients had a score of 0, thirteen had a score of 1, eleven had a score of 2, and fourteen had a score of 3. After 12 weeks of treatment (N\u0026thinsp;=\u0026thinsp;43) seventeen patient scored 0, fourteen scored 1, ten scored 2 and only two scored 3. These data are rendered in Fig.\u0026nbsp;1. After 12 weeks of depression treatment (N\u0026thinsp;=\u0026thinsp;43), 24 patients (55.8%) reported a lower pain score, 15 patients (34.9%) reported no change and 4 (9.3%) reported enhanced pain score. For the seven patients who dropped out, the pain scores at baseline were not significantly different from the other participants (Table\u0026nbsp;1).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003e3.2 Correlation between pain and depression\u003c/h2\u003e \u003cp\u003eAt baseline the depression scores were correlated with pain scores. The Spearman correlation coefficient (r) for pain score and MADRS at baseline was 0.363 (p\u0026thinsp;=\u0026thinsp;0.01), while for pain score and IDS it was 0.303 (p\u0026thinsp;=\u0026thinsp;0.03). After 12 weeks of treatment, pain scores and depression scores were no longer significantly correlated, with r\u0026thinsp;=\u0026thinsp;0.155 (p\u0026thinsp;=\u0026thinsp;0.32) for MADRS and r\u0026thinsp;=\u0026thinsp;0.235 (p\u0026thinsp;=\u0026thinsp;0.13) for IDS. The change in pain scores from baseline until after 12 weeks (Δ pain) were not significantly correlated with the change in depression scores (Δ MADRS and Δ IDS). See Table\u0026nbsp;2.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003e3.3 Pain and depression treatment outcome\u003c/h2\u003e \u003cp\u003eThe reduction in depression scores after 12 weeks of depression treatment was not significantly correlated to the pain level at baseline. For baseline, pain scores and the Δ MADRS the r was \u0026divide;\u0026thinsp;0.067, with a p-value of 0.67. For baseline pain scores and the Δ IDS the r was \u0026divide;\u0026thinsp;0.117 with a p-value of 0.45. The data are rendered in Table\u0026nbsp;2. We also compared change in MADRS and IDS from baseline till follow-up between those with low pain at baseline (score 0 and 1) and those with high pain at baseline (score 2 and 3). There was no difference between the two groups; the p-values were respectively 0.990 and 0.894.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003e3.4 Correlation between cytokines and pain\u003c/h2\u003e \u003cp\u003eThere was no correlation between cytokine levels and pain scores, neither at baseline nor after 12 weeks. The change in pain scores (significant lower after 12 weeks of treatment), was not correlated to the cytokine levels, neither at baseline nor at follow-up.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003e3.5 Treatment without medication\u003c/h2\u003e \u003cp\u003e The choice of treatment was not an object of this study, and was decided by therapist and patients, as recommended in the Norwegian national treatment guidelines. Out of the 43 who completed the 12 weeks of treatment, 29 did not use any medication and 14 were treated with antidepressants. There were no significant differences between these groups for MADRS, IDS, and pain scores at baseline or follow up (data not shown).\u003c/p\u003e \u003c/div\u003e"},{"header":"4 Discussion","content":"\u003cp\u003eOur main finding is that as many as three out of four depressed MDD patients experienced pain, and there was a significant drop in pain scores after 12 weeks of treatment as depression was relieved. We did not find that pain was associated with treatment effect, nor with cytokine levels.\u003c/p\u003e \u003cp\u003eOur finding of a high occurrence of pain in depression is in line with former findings [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan additionalcitationids=\"CR28\" citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. We also found that pain scores were correlated to depression severity before treatment, and that both depression and pain scores were significantly reduced after 12 weeks of depression treatment. However, the scores were no longer correlated after ended treatment. Altogether our findings indicate that pain is a feature of a MDD depressive episode. This may have an important clinical implication. In the RESPECT trial Kroenke and co-workers showed that \u0026ldquo;recognizing and optimizing the management of comorbid pain that commonly coexists with depression may be important in enhancing depression response and remission rates\u0026rdquo; [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eWe found that neither pain score at baseline nor change in pain score after treatment was correlated to depression treatment outcome. Further, no difference in depression treatment outcome between those with high and low pain scores at baseline was found. This indicates that pain does not seem to predict depression treatment outcome. These findings contrast with other findings [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eCytokines have been found to be involved in a \"glial-cytokine-neuronal interaction\", the underlying mechanism of persistent pain [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. We have earlier shown that the levels of various cytokines are elevated in a MDD depressive episode and normalized after recovery [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. In this present study we found indications for pain being a feature of depression. On the other hand, we found no correlations between cytokine levels and pain scores, neither at baseline nor after treatment. Further, cytokine levels were not correlated to the change in pain scores. Thus, we were not able to provide evidence for a possible causal relation between depression, cytokines and pain. There is a need for more research into the relation between cytokines and pain in depression. In a recent paper the support for a Psycho-Neuro-Endocrine-Immune basis for a placebo mediated analgesia and anxiolytic response is reviewed [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e].\u003c/p\u003e"},{"header":"5 Limitations","content":"\u003cp\u003eOne possible limitation of the present study might be that we assessed cytokines in peripheral blood, and pain is constituted of mechanisms both in the periphery and in the central nervous system. However, there are findings indicating a connection between peripherally assessed cytokines and cytokine activity in the brain. Former studies have shown that the blood brain barrier (BBB) is impeded by immune activation [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e], and there is evidence of a strong correlation between plasma and CSF levels of certain cytokines [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e, \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]. Cytokines produced and assessed elsewhere in the body are able to bind to receptors on brain immune cells, such as microglia, and further induce the expression of cytokines[\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e, \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]. In addition, an increase in serum cytokine levels have also been observed after non-neurological surgery that was accompanied by even higher cytokine levels in the cerebrospinal fluid (CSF) [\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e]. Another possible limitation is the relatively small number of individuals (N\u0026thinsp;=\u0026thinsp;50), making the study vulnerable to type II error. A further limitation may be that the patients were enrolled from a population referred with MDD to a specialized psychiatric outpatient clinic, making these results less relevant to other depressed patients.\u003c/p\u003e \u003cp\u003eOne strength of this study is that the patients were thoroughly screened for inflammatory and immunological diseases. Further, the patients were all free of medication at inclusion. This rules out the potential influence from other conditions and medication on the experienced pain and cytokine levels at baseline.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cem\u003eEthics approval and consent to participate\u003c/em\u003e:\u003c/p\u003e\n\u003cp\u003eThe study was approved by the local Ethics Committee: \u003cem\u003eRegional komite\u003c/em\u003e\u003cem\u003é\u003c/em\u003e\u003cem\u003e for medisinsk og helsefaglig forskningsetikk S\u0026oslash;r-\u0026Oslash;st C (REK S\u0026oslash;r-\u0026Oslash;st C), Postboks 1130 Blindern, NO-1130 Oslo, Norway\u003c/em\u003e. The patients provided written consent to participate after receiving verbal and written information regarding the study.\u003c/p\u003e\n\u003cp\u003eAll methods were performed in accordance with the relevant guidelines and regulations.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eAvailability of data and material\u003c/em\u003e:\u003c/p\u003e\n\u003cp\u003eThe dataset generated during and analyzed during the current study are not publicly available du to requirements from Regional Ethics Committee but are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eFunding\u003c/em\u003e:\u003c/p\u003e\n\u003cp\u003eThe study is fully funded by Ringerike Psychiatric Center and\u003c/p\u003e\n\u003cp\u003eVestre Viken Hospital Trust, Norway.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eAcknowledgements\u003c/em\u003e:\u003c/p\u003e\n\u003cp\u003eThe authors would like to thank Vestre Viken Hospital Trust and Ringerike Psychiatric Center for funding the study. We would also like to thank the South-Eastern Norway Regional Health Authority\u0026rsquo;s (HS\u0026Oslash;) Norwegian research network on\u003c/p\u003e\n\u003cp\u003emood disorders (NORMOOD) for initiating the study, and Tove H\u0026aelig;reid Otterstad for her coordination of the NORMOOD project. Further, we are indebted to Anne Skjerstein for\u003c/p\u003e\n\u003cp\u003etaking care of the blood samples and the logistics. Finally, we will express our gratitude to the patients that participated in the study.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eConsent for publication\u003c/em\u003e:\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eCompeting interests\u003c/em\u003e:\u003c/p\u003e\n\u003cp\u003eThe authors declare no conflict of interest.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eAuthors ̓ contributions\u003c/em\u003e:\u003c/p\u003e\n\u003cp\u003eJD, OAA, HO and UFM designed the study. JD and HCDA participated in data collection. JD analyzed the data. JD wrote the first draft of the manuscript. All co-authors interpreted the data, participated in revising the manuscript and approved the final version.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eKessler, R.C. and E.J. Bromet, \u003cem\u003eThe epidemiology of depression across cultures\u003c/em\u003e. Annu Rev Public Health, 2013. \u003cb\u003e34\u003c/b\u003e: p.\u0026nbsp;119\u0026ndash;38.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDworkin, S.F. and L. LeResche, \u003cem\u003eResearch diagnostic criteria for temporomandibular disorders: review, criteria, examinations and specifications, critique\u003c/em\u003e. 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J Affect Disord, 2009. \u003cb\u003e115\u003c/b\u003e(1\u0026ndash;2): p.\u0026nbsp;287\u0026ndash;92.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRaison, C.L., et al., \u003cem\u003eActivation of central nervous system inflammatory pathways by interferon-alpha: relationship to monoamines and depression\u003c/em\u003e. Biol Psychiatry, 2009. \u003cb\u003e65\u003c/b\u003e(4): p.\u0026nbsp;296\u0026ndash;303.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDantzer, R., et al., \u003cem\u003eNeural and humoral pathways of communication from the immune system to the brain: parallel or convergent?\u003c/em\u003e Auton Neurosci, 2000. \u003cb\u003e85\u003c/b\u003e(1\u0026ndash;3): p.\u0026nbsp;60\u0026ndash;5.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLoane, D.J. and K.R. Byrnes, \u003cem\u003eRole of microglia in neurotrauma\u003c/em\u003e. Neurotherapeutics, 2010. \u003cb\u003e7\u003c/b\u003e(4): p.\u0026nbsp;366\u0026ndash;77.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBromander, S., et al., \u003cem\u003eChanges in serum and cerebrospinal fluid cytokines in response to non-neurological surgery: an observational study\u003c/em\u003e. J Neuroinflammation, 2012. \u003cb\u003e9\u003c/b\u003e: p.\u0026nbsp;242.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTable 1. Symptom scores of depression and pain, pre- and post- treatment\u0026nbsp;\u003c/p\u003e\n\u003ctable width=\"0\"\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd width=\"113\"\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eVariable\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"123\"\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eWeek 0\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"123\"\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eWeek 12\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"113\"\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003ep\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"113\"\u003e\n\u003cp\u003e\u003cem\u003eIDS\u003c/em\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"123\"\u003e\n\u003cp\u003e37.1 (\u0026plusmn;8.2)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"123\"\u003e\n\u003cp\u003e18.6 (\u0026plusmn;12.0)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"113\"\u003e\n\u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"113\"\u003e\n\u003cp\u003e\u003cem\u003eMADRS\u003c/em\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"123\"\u003e\n\u003cp\u003e27.8 (\u0026plusmn;5.8)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"123\"\u003e\n\u003cp\u003e13.4 (\u0026plusmn;9.2)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"113\"\u003e\n\u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"113\"\u003e\n\u003cp\u003e\u003cem\u003ePain score\u003c/em\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"123\"\u003e\n\u003cp\u003e1.54 (\u0026plusmn;1.15)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"123\"\u003e\n\u003cp\u003e0.93 (\u0026plusmn;0.93)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"113\"\u003e\n\u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u0026nbsp;IDS= Inventory of Depressive Symptomatology\u0026nbsp;\u0026nbsp; MADRS= Montgomery Aasberg Depression Rating Scale\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;Table 2. Correlations\u0026nbsp;\u003c/p\u003e\n\u003ctable width=\"0\"\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd width=\"142\"\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eCorrelation between:\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"32\"\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"109\"\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"38\"\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"121\"\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"86\"\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"142\"\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"32\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"109\"\u003e\n\u003cp\u003eSpearman`s rho\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u003cem\u003ep-\u003c/em\u003evalue\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"38\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"121\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"86\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"142\"\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eBaseline pain and \u003c/em\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cem\u003e\u0026Delta;\u003c/em\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cem\u003e MADRS\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"32\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"109\"\u003e\n\u003cp\u003e\u0026divide; 0.067\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e0.67\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"38\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"121\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"86\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"142\"\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"32\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"109\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"38\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"121\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"86\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"142\"\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eBaseline pain\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eand \u003c/em\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cem\u003e\u0026Delta;\u003c/em\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cem\u003e IDS\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"32\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"109\"\u003e\n\u003cp\u003e\u0026divide;0.117\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e0.45\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"38\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"121\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"86\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"142\"\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"32\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"109\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"38\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"121\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"86\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"142\"\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003e\u0026Delta; \u003c/em\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cem\u003epain and\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003e\u0026Delta; \u003c/em\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cem\u003eMADRS \u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"32\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"109\"\u003e\n\u003cp\u003e0.460\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e0.77\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"38\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"121\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"86\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"142\"\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"32\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"109\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"38\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"121\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"86\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"142\"\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003e\u0026Delta;\u003c/em\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cem\u003e pain and\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003e\u0026Delta;\u003c/em\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cem\u003e IDS\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"32\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"109\"\u003e\n\u003cp\u003e0.137\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e0.38\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"38\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"121\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"86\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"142\"\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"32\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"109\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"38\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"121\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"86\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"142\"\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"32\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"185\"\u003e\n\u003cp\u003eWeek 0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"38\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"208\"\u003e\n\u003cp\u003eWeek 12\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"142\"\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"32\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"109\"\u003e\n\u003cp\u003eSpearman`s rho\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u003cem\u003ep-\u003c/em\u003evalue\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"38\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"121\"\u003e\n\u003cp\u003eSpearman`s rho\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"86\"\u003e\n\u003cp\u003e\u003cem\u003ep-\u003c/em\u003evalue\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"142\"\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003epain and MADRS\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"32\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"109\"\u003e\n\u003cp\u003e0.363\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u003cstrong\u003e0.01\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"38\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"121\"\u003e\n\u003cp\u003e0.155\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"86\"\u003e\n\u003cp\u003e0.32\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"142\"\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003epain and IDS\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"32\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"109\"\u003e\n\u003cp\u003e0.303\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u003cstrong\u003e0.03\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"38\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"121\"\u003e\n\u003cp\u003e0.235\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"86\"\u003e\n\u003cp\u003e0.13\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u0026Delta; = Change from baseline till follow-up\u003c/p\u003e\n\u003cp\u003eMADRS = Montgomery Aasberg Depression Rating Scale\u003c/p\u003e\n\u003cp\u003eIDS = Inventory of Depressive Symptomatology\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Pain in depression, cytokines, follow-up study, treatment outcome prediction","lastPublishedDoi":"10.21203/rs.3.rs-1659294/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-1659294/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eDepressed patients have an increased incidence of pain. A pathophysiological connection between depression and pain is still not revealed. Immunological activation has been found in both depression and pain. There are few studies of pain and immune activation in patients with depression, without inflammatory and autoimmune disorders\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eThis is a naturalistic follow-up study of 50 patients with a major depressive disorder (MDD) depressive episode, without any inflammatory or autoimmune conditions. We have previously reported on the relationship between depression and cytokine levels. In this study we obtained data of depression, pain and cytokine levels before and after 12 weeks of depression treatment. All patients were medication-free at inclusion.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eAt inclusion three out of four patients experienced pain, and the pain scores correlated with the depression scores. After treatment, as depression was relieved, the pain scores dropped significantly and were no longer correlated to the depression scores. There were no correlations between pain scores and cytokine levels. Pain level at inclusion did not correlate with depression treatment outcome.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eOur findings indicate that pain is a feature of depression. Pain levels and cytokine values didn`t correlate. Pain at inclusion did not predict depression treatment outcome.\u003c/p\u003e","manuscriptTitle":"Changes in pain during a depressive episode and relationship to cytokine levels in Major Depressive Disorder","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2022-05-24 16:30:30","doi":"10.21203/rs.3.rs-1659294/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"b2e8cb49-e212-43b1-92fb-3f49f0571a33","owner":[],"postedDate":"May 24th, 2022","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2024-04-01T23:05:46+00:00","versionOfRecord":{"articleIdentity":"rs-1659294","link":"https://doi.org/10.1080/08039488.2023.2290654","journal":{"identity":"nordic-journal-of-psychiatry","isVorOnly":true,"title":"Nordic Journal of Psychiatry"},"publishedOn":"2024-01-22 23:05:46","publishedOnDateReadable":"January 22nd, 2024"},"versionCreatedAt":"2022-05-24 16:30:30","video":"","vorDoi":"10.1080/08039488.2023.2290654","vorDoiUrl":"https://doi.org/10.1080/08039488.2023.2290654","workflowStages":[]},"version":"v1","identity":"rs-1659294","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-1659294","identity":"rs-1659294","version":["v1"]},"buildId":"7rjqhiLT3MXkJMwkYKINL","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}