SuPAR in major depression: Association with 26 weeks antidepressant response and 10-year depression outcomes.

Introduction: Inflammation has been associated with depression and differential antidepressant (AD) treatment response. Soluble urokinase plasminogen activator receptor (suPAR) is a novel measure of chronic inflammation. We investigated whether suPAR is associated with depression severity and AD response. Methods: We included 90 patients with major depressive disorder (MDD) who participated in a part-randomized clinical trial of 26 weeks of treatment with escitalopram or nortriptyline. suPAR levels were measured in serum samples collected at baseline and after 8, 12 and 26 weeks. Mixed effects models for the association between suPAR levels and AD response were performed. By merging with Danish nationwide registers, we included information on psychiatric hospital contacts during ten years after the GENDEP trial. Cox regression analyses calculated the hazard rate ratios between suPAR levels and subsequent hospitalizations. Results: At baseline, higher suPAR levels were not associated with overall depression severity but with greater severity of neurovegetative depressive symptoms, specifically appetite and weight changes. 57 (63.3%) patients responded positively to treatment. Among 57 (63.3%) patients who achieved response, those who responded had significantly higher baseline suPAR levels levels, and response was associated with a significant decrease in suPAR during AD treatment. Remitters decreased from 3.1 ng/ml at baseline to 2.8 ng/ml after 26 weeks (p = 0.003) and responders from 3.0 to 2.8 ng/ml (p = 0.02), whereas non-remitters and non-responders showed unchanged suPAR levels. We found no correlation between a change in suPAR and a change in MADRS, but a lowering of suPAR correlated with a decrease in neurovegetative symptoms. We found no association between suPAR levels and 10-year risk for hospitalizations. Discussion: The present study suggests that an elevated level of chronic inflammation, measured as the suPAR level, is associated with better response to AD treatment.

Efficacy of anti-inflammatory treatment on major depressive disorder or depressive symptoms: meta-analysis of clinical trials.

BACKGROUND: No study has gathered evidence from all randomized clinical trials (RCTs) with anti-inflammatory drugs measuring antidepressant effects including a detailed assessment of side-effects and bias. METHODS: We performed a systematic review identifying RCTs published prior to January 1, 2018, studying antidepressant treatment effects and side-effects of pharmacological anti-inflammatory intervention in adults with major depressive disorder (MDD) or depressive symptoms. Outcomes were depression scores after treatment, remission, response, and side-effects. Pooled standard mean differences (SMD) and risk ratios (RR) including 95% confidence intervals (95%-CI) were calculated. RESULTS: We identified 36 RCTs, whereof 13 investigated NSAIDs (N = 4214), 9 cytokine inhibitors (N = 3345), seven statins (N = 1576), 3 minocycline (N = 151), 2 pioglitazone (N = 77), and 2 glucocorticoids (N = 59). Anti-inflammatory agents improved depressive symptoms compared to placebo as add-on in patients with MDD (SMD = -0.64; 95%-CI = -0.88, -0.40; I2  = 51%; N = 597) and as monotherapy (SMD = -0.41; 95%-CI = -0.60, -0.22; I2  = 93%, N = 8825). Anti-inflammatory add-on improved response (RR = 1.76; 95%-CI = 1.44-2.16; I2  = 16%; N = 341) and remission (RR = 2.14; 95%-CI = 1.03-4.48; I2  = 57%; N = 270). We found a trend toward an increased risk for infections, and all studies showed high risk of bias. CONCLUSION: Anti-inflammatory agents improved antidepressant treatment effects. Future RCTs need to include longer follow-up, identify optimal doses and subgroups of patients that can benefit from anti-inflammatory intervention.

Mortality in unipolar depression preceding and following chronic somatic diseases.

OBJECTIVE: It is largely unknown how depression prior to and following somatic diseases affects mortality. Thus, we examined how the temporal order of depression and somatic diseases affects mortality risk. METHOD: Data were from a Danish population-based cohort from 1995 to 2013, which included all residents in Denmark during the study period (N = 4 984 912). Nineteen severe chronic somatic disorders from the Charlson Comorbidity Index were assessed. The date of first diagnosis of depression and somatic diseases was identified. Multivariable Cox proportional Hazard models with time-varying covariates were constructed to assess the risk for all-cause and non-suicide deaths for individual somatic diseases. RESULTS: For all somatic diseases, prior and/or subsequent depression conferred a significantly higher mortality risk. Prior depression was significantly associated with a higher mortality risk when compared to subsequent depression for 13 of the 19 somatic diseases assessed, with the largest difference observed for moderate/severe liver disease (HR = 2.08; 95% CI = 1.79-2.44), followed by metastatic solid tumor (HR = 1.48; 95% CI = 1.39-1.58), and myocardial infarction (HR = 1.40; 95% CI = 1.34-1.49). CONCLUSION: A particularly high mortality risk was observed in the presence of prior depression for most somatic diseases. Future studies that assess the underlying mechanisms are necessary to adequately address the excessive mortality associated with comorbid depression.

C-reactive protein and white blood cell levels in schizophrenia, bipolar disorders and depression - associations with mortality and psychiatric outcomes: a population-based study.

BACKGROUND: Mental disorders have been associated with increased levels of inflammatory markers, which can affect disease trajectories. We aimed to assess levels of C-reactive protein (CRP) and white blood cells (WBC) across individuals with schizophrenia, bipolar disorder, and depression, and to investigate associations with subsequent psychiatric admission and mortality. METHODS: We identified all adults in the Central Denmark Region during 2000-2012 with a first diagnosis of schizophrenia, bipolar disorder, or depression and a baseline measurement of CRP and/or WBC count. We followed these individuals until outcome of interest (psychiatric admission or death), emigration or December 31, 2012, using Cox regression analysis to estimate hazard ratios (HRs). RESULTS: Baseline median CRP differed significantly between mental disorders (P=0.01) being highest in individuals with bipolar disorder (3.5mg/L) (particularly during manic states, 3.9mg/L), followed by schizophrenia (3.1mg/L), and depression (2.8mg/L), while baseline WBC count did not differ (median 7.1×109/L). Elevated CRP levels were associated with increased all-cause mortality by adjusted HRs of 1.56 (95% CI: 1.02-2.38) for levels 3-10mg/L and 2.07 (95% CI: 1.30-3.29) for levels above 10mg/L compared to individuals with levels below 3mg/L. WBC counts were not associated with all-cause mortality. No association was observed between levels of the inflammatory markers and subsequent psychiatric admissions. CONCLUSIONS: People with severe mental disorders had increased inflammatory markers at first diagnosis, and elevated CRP levels were associated with increased mortality. Thorough screening for physical diseases is of utmost importance among individuals who are diagnosed with severe mental disorder.