Linking unfolded protein response to inflammation and depression: potential pathologic and therapeutic implications.
Ii Timberlake Matthew,Dwivedi Yogesh
Depression is a devastating mental disorder that affects millions of people worldwide. Inflammation has been shown to be a key factor involved in the underlying pathophysiology of depression and has been shown in a substantial proportion of cases of depression. Changes attributed with morphological deformities and immunomodulation in susceptible regions of the depressed brain raised the possibility of altered cellular homeostasis transduced by the intracellular stress response. How emotional stressors can lead to an inflamed brain that directly affects physiology and activity is yet to be fully understood. The unfolded protein response (UPR) has been shown to be active in both models of depression as well as in postmortem brain of depressed individuals. The UPR is the cellular response to stress which results in misfolded proteins. Interestingly, UPR activation is directly linked to both inflammatory cytokine production and Toll-like receptor (TLR) expression. The TLRs are part of the innate immune response which typically reacts to "classic invasions" such as bacteria or viruses as well as trauma. TLRs have also been shown to be upregulated in depression, thus solidifying the connection between inflammation and depression. In this review, we aim to tie the UPR-TLR response and depression, and describe the implications of such an association. We also propose future directions for their role in treatment for depression.
Depression and obesity: evidence of shared biological mechanisms.
Depression and obesity are common conditions with major public health implications that tend to co-occur within individuals. The relationship between these conditions is bidirectional: the presence of one increases the risk for developing the other. It has thus become crucial to gain a better understanding of the mechanisms responsible for the intertwined downward physiological spirals associated with both conditions. The present review focuses specifically on shared biological pathways that may mechanistically explain the depression-obesity link, including genetics, alterations in systems involved in homeostatic adjustments (HPA axis, immuno-inflammatory activation, neuroendocrine regulators of energy metabolism including leptin and insulin, and microbiome) and brain circuitries integrating homeostatic and mood regulatory responses. Furthermore, the review addresses interventional opportunities and questions to be answered by future research that will enable a comprehensive characterization and targeting of the biological links between depression and obesity.
Elevated C-Reactive Protein in Patients With Depression, Independent of Genetic, Health, and Psychosocial Factors: Results From the UK Biobank.
The American journal of psychiatry
OBJECTIVE:The authors investigated the pathways (genetic, environmental, lifestyle, medical) leading to inflammation in major depressive disorder using C-reactive protein (CRP), genetic, and phenotypic data from the UK Biobank. METHODS:This was a case-control study of 26,894 participants with a lifetime diagnosis of major depressive disorder from the Composite International Diagnostic Interview and 59,001 control subjects who reported no mental disorder and had not reported taking any antidepressant medication. Linear regression models of log CRP level were fitted to regress out the effects of age, sex, body mass index (BMI), and smoking and to test whether the polygenic risk score (PRS) for major depression was associated with log CRP level and whether the association between log CRP level and major depression remained after adjusting for early-life trauma, socioeconomic status, and self-reported health status. RESULTS:CRP levels were significantly higher in patients with depression relative to control subjects (2.4 mg/L compared with 2.1 mg/L, respectively), and more case than control subjects had CRP levels >3 mg/L (21.2% compared with 16.8%, respectively), indicating low-grade inflammation. The PRS for depression was positively and significantly associated with log CRP levels, but this association was no longer significant after adjustment for BMI and smoking. The association between depression and increased log CRP level was substantially reduced, but still remained significant, after adjustment for the aforementioned clinical and sociodemographic factors. CONCLUSIONS:The data indicate that the "genetic" contribution to increased inflammation in depression is due to regulation of eating and smoking habits rather than an "autoimmune" genetic predisposition. Moreover, the association between depression and increased inflammation even after full adjustment indicates either the presence of yet unknown or unmeasured psychosocial and clinical confounding factors or that a core biological association between depression and increased inflammation exists independently from confounders.
Sex differences in the association of baseline c-reactive protein (CRP) and acute-phase treatment outcomes in major depressive disorder: Findings from the EMBARC study.
Jha Manish K,Minhajuddin Abu,Chin-Fatt Cherise,Greer Tracy L,Carmody Thomas J,Trivedi Madhukar H
Journal of psychiatric research
Peripheral inflammation is associated with poor response to antidepressant treatments. However, whether sex differentially affects this association remains unknown. Participants of Establishing Moderators and Biosignatures of Antidepressant Response for Clinical Care (EMBARC) with baseline plasma samples were included in this study (n = 220; male n = 75, female n = 145). Depression severity [Hamilton Rating Scale for Depression 17-item (HAMD-17)] was measured at baseline and weeks- 1, 2, 3, 4, 6, and 8. Plasma c-reactive protein (CRP) was measured with commercially-available ELISA kits at baseline, week-1, and week-8. Sex difference in prediction of baseline-to-week-8 HAMD-17 change by baseline CRP was tested with sex-by-baseline-CRP-by-time interaction in mixed model analysis. Additionally, changes in CRP from baseline-to-week-8 CRP and its association with HAMD-17 changes over that period were also evaluated. Covariates included body mass index, site, smoking status, and age. There was a significant sex difference in association of baseline-to-week-8 HAMD-17 reduction with baseline CRP (p = 0.033). Higher baseline CRP was associated with lower baseline-to-week-8 HAMD-17 reduction in females (p < 0.0001) but not in males (p = 0.632). Additionally, CRP was significantly reduced (p = 0.041, effect size = 0.254) from baseline-to-week-8, but there were no sex differences in this reduction (p = 0.249). Baseline-to-week-8 changes in HAMD-17 and CRP were not significantly associated either overall (p = 0.348) or based on sex (p = 0.370). In a large study of depressed outpatients, we replicated previous findings that elevated baseline CRP levels are associated with worse antidepressant treatment outcomes. However, this effect was limited only to females. These findings emphasize the importance of studying sex differences in biological mechanisms linking inflammation and depression.
Role of Interleukin-6 in Depressive Disorder.
Ting Emily Yi-Chih,Yang Albert C,Tsai Shih-Jen
International journal of molecular sciences
Major depressive disorder (MDD), which is a leading psychiatric illness across the world, severely affects quality of life and causes an increased incidence of suicide. Evidence from animal as well as clinical studies have indicated that increased peripheral or central cytokine interleukin-6 (IL-6) levels play an important role in stress reaction and depressive disorder, especially physical disorders comorbid with depression. Increased release of IL-6 in MDD has been found to be a factor associated with MDD prognosis and therapeutic response, and may affect a wide range of depressive symptomatology. However, study results of the genetic effects in MDD are controversial. Increased IL-6 activity may cause depression through activation of hypothalamic-pituitary-adrenal axis or influence of the neurotransmitter metabolism. The important role of neuroinflammation in MDD pathogenesis has created a new perspective that the combining of blood IL-6 and other depression-related cytokine levels may help to classify MDD biological subtypes, which may allow physicians to identify the optimal treatment for MDD patients. To modulate the IL-6 activity by IL-6-related agents, current antidepressive agents, herb medication, pre-/probiotics or non-pharmacological interventions may hold great promise for the MDD patients with inflammatory features.
C-Reactive Protein as a Biomarker for Major Depressive Disorder?
Orsolini Laura,Pompili Simone,Tempia Valenta Silvia,Salvi Virginio,Volpe Umberto
International journal of molecular sciences
The etiopathogenesis of depression is not entirely understood. Several studies have investigated the role of inflammation in major depressive disorder. The present work aims to review the literature on the association between C-Reactive Protein (CRP) and depression. A systematic review was performed for the topics of 'CRP' and 'depression' using the PubMed database from inception to December 2021. Fifty-six studies were identified and included in the review. Evidence suggested the presence of dysregulation in the inflammation system in individuals with depression. In most studies, higher blood CRP levels were associated with greater symptom severity, a specific pattern of depressive symptoms, and a worse response to treatment. Moreover, about one-third of depressed patients showed a low-grade inflammatory state, suggesting the presence of a different major depressive disorder (MDD) subgroup with a distinct etiopathogenesis, clinical course, treatment response, and prognosis, which could benefit from monitoring of CRP levels and might potentially respond to anti-inflammatory treatments. This work provides robust evidence about the potential role of CRP and its blood levels in depressive disorders. These findings can be relevant to developing new therapeutic strategies and better understanding if CRP may be considered a valuable biomarker for depression.