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Exploring Links between Melatonin, Inflammation and Depression
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Psychiatry, University Hospital.ORCID iD: 0000-0003-3271-0456
2019 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Major depressive disorder (MDD) is one of the leading global causes of disease burden. Worse yet, about one third of the patients with MDD do not experience a remission with current treatments. The symptoms of MDD likely represent a variety of underlying pathologic processes and more knowledge about these processes is needed to optimize treatment for MDD. The focus of this thesis was to study the relationship between inflammation, melatonin and symptoms of depression. 

In papers I-III a population of young adults seeking psychiatric care was examined for depressive symptoms, melatonin levels in saliva, gastrointestinal (GI) symptoms and inflammatory markers in blood. In paper IV a cohort of patients with hepatitis C receiving treatment with new direct-acting agents (DAAs) were prospectively followed during treatment for depressive symptoms and sleep.

All patients were diagnosed by means of structured or semi-structured interviews and depressive symptoms were assessed with the self-rating version of the Montgomery Åsberg Depression Rating Scale. Sleep quality was measured by the Pittsburgh Sleep Quality Index, and GI symptoms were assessed with the Gastrointestinal Symptom Rating Scale-IBS. Melatonin in saliva was measured using enzyme-linked immunosorbent assay, and inflammatory markers in blood were analysed by proximity extension assay.

In young adults seeking psychiatric care melatonin levels at bedtime were inversely correlated with depressive symptoms. In those patients with a current depressive episode low melatonin values at bedtime were a negative prognostic factor for response after 6 months (paper I). Postprandial melatonin levels were positively associated with GI symptoms of bloating and pain (paper II). Postprandial melatonin levels were also associated with the inflammatory markers vascular endothelial growth factor A (VEGF-A), monocyte chemoattractant protein-1 (MCP-1) and monocyte inflammatory protein-1α (MIP-1α). Evening levels of melatonin did not correlate with the inflammatory markers. VEGF-A and MCP-1 as well as postprandial levels of melatonin correlated with a diagnosis of anxiety disorder, whereas MIP-1α correlated with MDD (paper III). Patients with hepatitis C underwent treatment with DAAs without experiencing pronounced psychiatric side effects in terms of depressive symptoms or sleep disturbances (paper IV).

In summary, the findings confirm a relationship between bedtime melatonin levels and depressive symptoms. The findings also show a connection between daytime melatonin and GI-symptoms. In addition, the findings indicate an association between inflammation and daytime melatonin. Together these results demonstrate links between melatonin, inflammation and depression. Lastly, interferon-free treatment against hepatitis C did not induce depressive symptoms.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2019. , p. 70
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1526
Keywords [en]
melatonin, inflammation, depression, biomarkers, cytokines, anxiety, hepatitis C
National Category
Psychiatry
Research subject
Psychiatry
Identifiers
URN: urn:nbn:se:uu:diva-369411ISBN: 978-91-513-0535-6 (print)OAI: oai:DiVA.org:uu-369411DiVA, id: diva2:1270318
Public defence
2019-02-15, Sal IV, Universitetshuset, Biskopsgatan 3, Uppsala, 09:00 (Swedish)
Opponent
Supervisors
Available from: 2019-01-25 Created: 2018-12-12 Last updated: 2019-02-18
List of papers
1. Salivary Melatonin in Relation to Depressive Symptom Severity in Young Adults.
Open this publication in new window or tab >>Salivary Melatonin in Relation to Depressive Symptom Severity in Young Adults.
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2016 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 4, article id e0152814Article in journal (Refereed) Published
Abstract [en]

Reduced levels of melatonin have been associated with severe depression. The aim was to investigate the correlation between salivary melatonin and dimensional measures of depressive symptom severity in young adult psychiatric patients. Levels of melatonin were analyzed in six saliva samples during waking hours from 119 young adult patients under outpatient psychiatric care. Melatonin levels were tested for association with the severity of depressive symptoms using the self-rating version of the Montgomery Åsberg Depression Rating Scale (MADRS-S). Where possible, depressive symptoms were assessed again after 6±2 months of treatment. Response was defined as decrease in MADRS-S by ≥50% between baseline and follow-up. Patients with levels of melatonin in the lowest quartile at bedtime had an increased probability of a high MADRS-S score compared to those with the highest levels of melatonin (odds ratio 1.39, 95% CI 1.15-1.69, p<0.01). A post hoc regression analysis found that bedtime melatonin levels predicted response (odds ratio 4.4, 95% CI 1.06-18.43, p<0.05). A negative relationship between salivary melatonin and dimensional measures of depressive symptom severity was found in young patients under outpatient psychiatric care. Bedtime salivary melatonin levels may have prognostic implications.

Keywords
Melatonin, Depression, Depressive Symptoms, Saliva, Severity, Prognosis, MADRS-S, Sheehan Disability Scale, HbA1C, Oxi-LDL, Research Domain Criteria (RDoC)
National Category
Psychiatry Neurosciences
Research subject
Psychiatry
Identifiers
urn:nbn:se:uu:diva-291425 (URN)10.1371/journal.pone.0152814 (DOI)000373592100035 ()27042858 (PubMedID)
Projects
Uppsala Psykiatriska Provsamling
Funder
Swedish Society of Medicine
Available from: 2016-05-02 Created: 2016-05-02 Last updated: 2018-12-12Bibliographically approved
2. Daytime Salivary Melatonin Related to Gastrointestinal Symptoms in Young Adults Seeking Psychiatric Care
Open this publication in new window or tab >>Daytime Salivary Melatonin Related to Gastrointestinal Symptoms in Young Adults Seeking Psychiatric Care
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2018 (English)In: Biological Psychiatry, ISSN 0006-3223, E-ISSN 1873-2402, Vol. 83, no 9, p. S185-S186Article in journal, Meeting abstract (Other academic) Published
Keywords
Melatonin, Irritable Bowel Syndrome, Depression
National Category
Psychiatry Gastroenterology and Hepatology
Identifiers
urn:nbn:se:uu:diva-361431 (URN)000432466300462 ()
Conference
73rd Annual Scientific Convention and Meeting of the Society-of-Biological-Psychiatry (SOBP), 2018, New York, NY
Available from: 2018-12-10 Created: 2018-12-10 Last updated: 2018-12-12Bibliographically approved
3. Daytime Melatonin Levels in Saliva are Associated with Inflammatory Markers and Anxiety Disorders in Young Adults with Psychiatric Disease
Open this publication in new window or tab >>Daytime Melatonin Levels in Saliva are Associated with Inflammatory Markers and Anxiety Disorders in Young Adults with Psychiatric Disease
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

The bidirectional interaction between melatonin and the immune system has largely gone unexplored in a clinical context and especially in a psychiatric population. This study explored the association between melatonin during the day and inflammatory cytokines in young adult patients seeking psychiatric care. Samples and data were collected from 108 young adults (mean age 21, SD=2) at an outpatient clinic for affective disorders. Daytime saliva melatonin levels were analyzed with enzyme-linked immunosorbent assay in relation to normalized serum expression levels of 72 inflammatory markers in a proximity extension assay. In a post hoc analysis, the markers with a significant association with melatonin were tested in a generalized linear model to see whether there is a relationship to anxiety disorder or depression. After Bonferroni correction for multiple testing, melatonin levels at 11:00 were positively correlated with cluster of differentiation 5 (CD5; p=4.2e-4, p adj=0.03). Melatonin levels after lunch were correlated with monocyte chemoattractant protein-1 (MCP-1; p=4.2e-4p adj=0.03), monocyte inflammatory protein-1 alpha (MIP-1α; p=6.5e-4p adj=0.047) and vascular endothelial growth factor A (VEGF-A; p=5.3e-6p adj=0.004). In the generalized linear model, positive associations were found between the presence of any anxiety disorder after lunch and melatonin (p=0.046), VEGF-A (p=0.001) and MIP-1α (p=0.001). Daytime saliva levels of melatonin were related to several inflammatory markers in psychiatric patients. This observation likely reflects the bidirectional relationship between melatonin production and the immune system. These findings may have relevance for the understanding of psychiatric disorders and other disorders associated with the same underlying pathogenesis, including low-grade inflammation.

National Category
Psychiatry
Research subject
Psychiatry
Identifiers
urn:nbn:se:uu:diva-369409 (URN)
Available from: 2018-12-12 Created: 2018-12-12 Last updated: 2018-12-12
4. Direct-acting antiviral treatment in real world patients with hepatitis C not associated with psychiatric side effects: a prospective observational study
Open this publication in new window or tab >>Direct-acting antiviral treatment in real world patients with hepatitis C not associated with psychiatric side effects: a prospective observational study
2018 (English)In: BMC Psychiatry, ISSN 1471-244X, E-ISSN 1471-244X, Vol. 18, article id 157Article in journal (Refereed) Published
Abstract [en]

Background: Treatment of Hepatitis C virus (HCV) infection has evolved from interferon (IFN)-based treatments to direct-acting antivirals (DAAs). Patients with HCV have an elevated psychiatric morbidity (including substance abuse) and patients with such comorbidity have often been excluded from treatment with IFN. To date, little is known about psychiatric adverse effects of DAA-based regimens. We therefore aimed to study the psychiatric side effects of new IFN-free treatment for HCV (including depressive symptoms and sleep) in real world patients also including those with a history of psychiatric diagnosis, substance abuse or drug dependence. Methods: Consecutive patients were monitored during treatment with three of the latest DAA agents (sofosbuvir, simeprevir and daclatasvir). Repeated expert psychiatric assessments from baseline to 12 weeks post-treatment were performed with the Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-I) clinical version and the self-report versions of the Montgomery Asberg Depression Rating Scale (MADRS-S) and the Pittsburgh Sleep Quality Index (PSQI). Friedman's test was performed to calculate differences in the MADRS-S and PSQI over time. In a post-hoc analysis Wilcoxon's test was used to compare baseline depressive symptoms with those at post-treatment. Spearman's rank correlation test was conducted in another post-hoc analysis to evaluate the correlation between symptoms of depression and HCV viral load at baseline. Results: At baseline, 15/17 patients (88%) had a history of any psychiatric diagnosis; 11 (65%) had a history of substance abuse or dependence; and 11 (65%) had previously been treated with IFN and six of those had experienced psychiatric side effects. There was no correlation between depressive symptoms and HCV viral load at baseline. Symptoms of depression did not increase during DAA treatment and were lower 12 weeks post-treatment compared with baseline: MADRS-S 10.7 vs. 8.3 (p = 0.01). This observation held when excluding patients taking antidepressant medication. Sleep quality did not significantly change during treatment. Adherence to treatment was estimated to 95% and sustained virological response was 88%. Conclusions: Despite high psychiatric morbidity, including previous substance abuse, patients successfully completed DAA treatment without increasing depressive symptoms or sleep disturbance. Symptoms of depression were significantly reduced 12 weeks after DAA treatment.

Keywords
Hepatitis C virus, Direct-acting antiviral, Depression, Sleep, Side effects
National Category
Psychiatry
Identifiers
urn:nbn:se:uu:diva-357557 (URN)10.1186/s12888-018-1735-6 (DOI)000433388700005 ()29843679 (PubMedID)
Funder
Swedish Society of MedicineFredrik och Ingrid Thurings StiftelseErik, Karin och Gösta Selanders Foundation
Available from: 2018-08-20 Created: 2018-08-20 Last updated: 2018-12-12Bibliographically approved

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