•Patients with depression show reduced variability in pro-inflammatory immune measures.•Patients with depression show increases in pro-inflammatory immune markers mean levels, and reductions in ...anti-inflammatory IL-4.
The magnitude and variability of cytokine alterations in depression are not clear.
To perform an up to date meta-analysis of mean differences of immune markers in depression, and to quantify and test for evidence of heterogeneity in immune markers in depression by conducting a meta-analysis of variability to ascertain whether only a sub-group of patients with depression show evidence of inflammation.
Studies that reported immune marker levels in peripheral blood in patients with depression and matched healthy controls in the MEDLINE database from inception to August 29th 2018 were examined.
Case-control studies that reported immune marker levels in peripheral blood in patients with depression and healthy controls were selected.
Means and variances (SDs) were extracted for each measure to calculate effect sizes, which were combined using multivariate meta-analysis.
Hedges g was used to quantify mean differences. Relative variability of immune marker measurements in patients compared with control groups as indexed by the coefficient of variation ratio (CVR).
A total of 107 studies that reported measurements from 5,166 patients with depression and 5,083 controls were included in the analyses. Levels of CRP (g = 0.71; 95%CI: 0.50–0.92; p < 0.0001); IL-3 (g = 0.60; 95%CI: 0.31–0.89; p < 0.0001); IL-6 (g = 0.61; 95%CI: 0.39–0.82; p < 0.0001); IL-12 (g = 1.18; 95%CI: 0.74–1.62; p < 0.0001); IL-18 (g = 1.97; 95%CI: 1.00–2.95; p < 0.0001); sIL-2R (g = 0.71; 95%CI: 0.44–0.98; p < 0.0001); and TNFα (g = 0.54; 95%CI: 0.32–0.76; p < 0.0001) were significantly higher in patients with depression. These findings were robust to a range of potential confounds and moderators. Mean-scaled variability, measured as CVR, was significantly lower in patients with depression for CRP (CVR = 0.85; 95%CI: 0.75–0.98; p = 0.02); IL-12 (CVR = 0.61; 95%CI: 0.46–0.80; p < 0.01); and sIL-2R (CVR = 0.85; 95%CI: 0.73–0.99; p = 0.04), while it was unchanged for IL-3, IL-6, IL-18, and TNF α.
Depression is confirmed as a pro-inflammatory state. Some of the inflammatory markers elevated in depression, including CRP and IL-12, show reduced variability in patients with depression, therefore supporting greater homogeneity in terms of an inflammatory phenotype in depression. Some inflammatory marker elevations in depression do not appear due to an inflamed sub-group, but rather to a right shift of the immune marker distribution.
Immune parameters are elevated in psychosis, but it is unclear whether alterations are homogenous across patients or heterogeneity exists, consistent with the hypothesis that immune alterations are ...specific to a subgroup of patients. To address this, we examine whether antipsychotic-naïve first-episode psychosis patients exhibit greater variability in blood cytokines, C-reactive protein, and white cell counts compared with controls, and if group mean differences persist after adjusting for skewed data and potential confounds. Databases were searched for studies reporting levels of peripheral immune parameters. Means and variances were extracted and analyzed using multivariate meta-analysis of mean and variability of differences. Outcomes were (1) variability in patients relative to controls, indexed by variability ratio (VR) and coefficient of variation ratio (CVR); (2) mean differences indexed by Hedges g; (3) Modal distribution of raw immune parameter data using Hartigan's unimodality dip test. Thirty-five studies reporting on 1263 patients and 1470 controls were included. Variability of interleukin-6 (IL6) (VR = 0.19), tumor necrosis factor-α (TNFα) (VR = 0.36), interleukin-1β (VR = 0.35), interleukin-4 (VR = 0.55), and interleukin-8 (VR = 0.28) was reduced in patients. Results persisted for IL6 and IL8 after mean-scaling. Ninety-four percent and one hundred percent of raw data were unimodally distributed in psychosis and controls, respectively. Mean levels of IL6 (g = 0.62), TNFα (g = 0.56), interferon-γ (IFNγ) (g = 0.32), transforming growth factor-β (g = 0.53), and interleukin-17 (IL17) (g = 0.48) were elevated in psychosis. Sensitivity analyses indicated this is unlikely explained by confounders for IL6, IFNγ, and IL17. These findings show elevated cytokines in psychosis after accounting for confounds, and that the hypothesis of an immune subgroup is not supported by the variability or modal distribution.
•Up-to 40% acute psychiatric inpatients show evidence of low-grade inflammation.•Low-grade inflammation is present in all ICD-10 major psychiatric diagnostic groups.•Older age increases inflammation, ...while being married appears to be protective.•Inflammation is associated with diagnosis of schizophrenia and bipolar disorder.•Inflammation is associated with prescribed antidepressants and medical comorbidity.
Low-grade inflammation is a risk factor for depression, psychosis and other major psychiatric disorders. It is associated with poor response to antidepressant and antipsychotics, and could potentially be a treatment target. However, there is limited data on the prevalence of low-grade inflammation in major psychiatric disorders, and on the characteristics of patients who show evidence of inflammation. We examined the prevalence of low-grade inflammation and associated socio-demographic and clinical factors in acute psychiatric inpatients.
An anonymised search of the electronic patient records of Cambridgeshire and Peterborough NHS Foundation Trust was used to identify patients aged 18–65 years who were hospitalised between 2013 and 2016 (inclusive). We excluded patients on antibiotics or oral steroids, or with missing data. Inflammation was defined using serum C-reactive protein (>3 mg/L) or total white cell count (>9.4 × 109/L) as measured within 14 days of admission.
Out of all 599 admissions, the prevalence of inflammation (serum CRP >3 mg/L) in the ICD-10 diagnostic groups of psychotic disorders (F20–29), mood disorders (F30–39), neurotic disorders (F40–48) and personality disorders (F60–69) was 32%, 21%, 22% and 42%, respectively. In multivariable analyses, low-grade inflammation was associated with older age, black ethnicity, being single, self-harm, diagnoses of schizophrenia, bipolar disorder, current treatments with antidepressants, benzodiazepines, and with current treatment for medical comorbidities.
A notable proportion of acutely unwell psychiatric patients from all ICD-10 major diagnostic groups show evidence of low-grade inflammation, suggesting inflammation may be relevant for all psychiatric disorders.
•A meta-analysis of mean differences and variability assessing peripheral levels of CRP, TNF-α, IL-1β, and IL-6 in individuals with BD and controls was conducted.•Levels of IL-1β were unaltered ...relative to controls.•Levels of IL-6, TNF-α and CRP were elevated in acute mood states relative to controls.•Only levels of IL-6 were elevated regardless of mood states (trait marker).•Our findings provide evidence that BD is characterized by peripheral immune activation.
It is unclear whether differences exist in the magnitude and variability of pro-inflammatory mediators in the different phases of bipolar disorder (BD) and among subjects with BD, as compared to healthy controls.
To run a comparative meta-analysis of C-Reactive Protein (CRP), IL-1, IL-6, TNF-α in BD vs healthy controls, measuring mean and variability effects on all subjects. Sensitivity analyses include disease activity.
Systematic review of observational studies in PubMed and PsycInfo up to February 2nd, 2020.
Case-control studies reporting inflammatory mediators' levels in BD and controls.
Summary distribution measures of circulating CRP, IL-1β, IL-6, TNF-α in participants with BD and control groups were extracted. Random-effects multivariate meta-analyses were conducted based on individual study/mediator effect sizes (Hedge’s g).
Co-primary outcomes were inflammatory mediators' levels (Hedge’s g) and variability (coefficient of variance ratio (CVR)) differences between participants with BD across the mood spectrum and controls.
Out of the initial 729 papers, 72 were assessed and then excluded after full-text review, and ultimately 53 studies were included in the systematic review, while 49 were included in the meta-analysis. The mean age was 36.96 (SD: 9.29) years, and the mean female percentage was 56.31 (SD: 16.61). CRP (g = 0.70, 95% CI 0.31–1.09, k = 37, BD = 2,215 vs HC = 3,750), IL-6 (g = 0.81, 95% CI 0.46–1.16, k = 45, BD = 1,956 vs HC = 4,106), TNF-α (g = 0.49, 95% CI 0.19–0.78, k = 49, BD = 2,231 vs HC = 3,017) were elevated in subjects with BD vs HC, but not IL-1β (g = -0.28, 95% CI −0.68–0.12, k = 4, BD = 87 vs HC = 66). When considering euthymic, depressive, and manic episodes separately, CRP and TNF-α were elevated in both depressive and manic episodes, but not in euthymia, while IL-6 remained elevated regardless of the disease state. No difference in CVR emerged for CRP, IL-1β, and TNF-α, while a lower CVR was observed for IL-6. When considering disease phases, CVR was higher in BD than in HCs for CRP during depressive episodes, lower for IL-6 during euthymia, and higher during manic episodes for CRP, IL-6, and TNF-α. Sensitivity analyses after excluding outliers identified with funnel plot visual inspection, low-quality studies, and considering only studies matched per body mass index confirmed the main results. Meta-regression showed that age (IL-6, TNF-α), gender (CRP), duration of illness (CRP) moderated elevated individual inflammatory levels.
Peripheral pro-inflammatory marker elevations were confirmed in BD. CRP and TNF-α could represent state markers, as they were only elevated during mood episodes, while IL-6 appeared to be a trait marker for BD. Increased variability of specific inflammatory mediators in specific disease active states suggests that a subset of subjects with BD may exhibit elevated inflammation as part of a manic or depressive episode.
COVID-19 has affected social interaction and healthcare worldwide.
We examined changes in presentations and referrals to the primary provider of mental health and community health services in ...Cambridgeshire and Peterborough, UK (population ~0·86 million), plus service activity and deaths. We conducted interrupted time series analyses with respect to the time of UK “lockdown”, which was shortly before the peak of COVID-19 infections in this area. We examined changes in standardized mortality ratio for those with and without severe mental illness (SMI).
Referrals and presentations to nearly all mental and physical health services dropped at lockdown, with evidence for changes in both supply (service provision) and demand (help-seeking). This was followed by an increase in demand for some services. This pattern was seen for all major forms of presentation to liaison psychiatry services, except for eating disorders, for which there was no evidence of change. Inpatient numbers fell, but new detentions under the Mental Health Act were unchanged. Many services shifted from face-to-face to remote contacts. Excess mortality was primarily in the over-70s. There was a much greater increase in mortality for patients with SMI, which was not explained by ethnicity.
COVID-19 has been associated with a system-wide drop in the use of mental health services, with some subsequent return in activity. “Supply” changes may have reduced access to mental health services for some. “Demand” changes may reflect a genuine reduction of need or a lack of help-seeking with pent-up demand. There has been a disproportionate increase in death among those with SMI during the pandemic.
Heart disease is the leading cause of death in schizophrenia. However, there has been little research directly examining cardiac function in schizophrenia.
To investigate cardiac structure and ...function in individuals with schizophrenia using cardiac magnetic resonance imaging (CMR) after excluding medical and metabolic comorbidity.
In total, 80 participants underwent CMR to determine biventricular volumes and function and measures of blood pressure, physical activity and glycated haemoglobin levels. Individuals with schizophrenia ('patients') and controls were matched for age, gender, ethnicity and body surface area.
Patients had significantly smaller indexed left ventricular (LV) end-diastolic volume (effect size d = -0.82, P = 0.001), LV end-systolic volume (d = -0.58, P = 0.02), LV stroke volume (d = -0.85, P = 0.001), right ventricular (RV) end-diastolic volume (d = -0.79, P = 0.002), RV end-systolic volume (d = -0.58, P = 0.02), and RV stroke volume (d = -0.87, P = 0.001) but unaltered ejection fractions relative to controls. LV concentricity (d = 0.73, P = 0.003) and septal thickness (d = 1.13, P < 0.001) were significantly larger in the patients. Mean concentricity in patients was above the reference range. The findings were largely unchanged after adjusting for smoking and/or exercise levels and were independent of medication dose and duration.
Individuals with schizophrenia show evidence of concentric cardiac remodelling compared with healthy controls of a similar age, gender, ethnicity, body surface area and blood pressure, and independent of smoking and activity levels. This could be contributing to the excess cardiovascular mortality observed in schizophrenia. Future studies should investigate the contribution of antipsychotic medication to these changes.
•Using CRP data from age 9, 15 and 18 we identified four population subgroups.•The subgroups represent persistently low, persistently high; decreasing; increasing CRP levels.•Increasing CRP levels ...were associated with moderate/severe depression at age 18.
Meta-analyses confirm increased circulating C-reactive protein (CRP) levels in depression. Longitudinal studies have linked one-off measurements of CRP at baseline with increased risk of developing depressive symptoms subsequently at follow-up, but studies with repeat CRP measures from the same individuals are scarce.
We have examined whether longitudinal patterns of inflammation, based on three CRP measurements from childhood to early-adulthood, are associated with the risk of depression in early-adulthood in the Avon Longitudinal Study of Parents and Children, a prospective birth cohort.
Using Gaussian mixture modelling of available CRP data from age 9, 15 and 18 years, we identified four population clusters/sub-groups reflecting different longitudinal patterns of CRP: persistently low (N=463, 29.5%); persistently high (N=371, 24%); decreasing (N=360, 23%); increasing (N=367, 23.5%). The increasing group showed a steep increase in CRP levels between adolescence and early-adulthood. Participants in this group had a higher risk of moderate/severe depression at age 18 years, compared with those with persistently low CRP; adjusted odds ratio (OR)=3.78 (95% Confidence Interval (CI), 1.46–9.81; p=0.006). The odds of moderate/severe depression were also increased for the persistently high CRP group, but this was not statistically significant; OR=2.54 (95% CI, 0.90–7.16).
Repeat CRP measures were available for a subset, who may not be representative of all cohort participants.
The results suggest that an increasing pattern of inflammation from adolescence to early-adulthood is associated with risk of depression in early-adulthood.
The use of clinical prediction models to produce individualized risk estimates can facilitate the implementation of precision psychiatry. As a source of data from large, clinically representative ...patient samples, electronic health records (EHRs) provide a platform to develop and validate clinical prediction models, as well as potentially implement them in routine clinical care. The current review describes promising use cases for the application of precision psychiatry to EHR data and considers their performance in terms of discrimination (ability to separate individuals with and without the outcome) and calibration (extent to which predicted risk estimates correspond to observed outcomes), as well as their potential clinical utility (weighing benefits and costs associated with the model compared to different approaches across different assumptions of the number needed to test). We review 4 externally validated clinical prediction models designed to predict psychosis onset, psychotic relapse, cardiometabolic morbidity, and suicide risk. We then discuss the prospects for clinically implementing these models and the potential added value of integrating data from evidence syntheses, standardized psychometric assessments, and biological data into EHRs. Clinical prediction models can utilize routinely collected EHR data in an innovative way, representing a unique opportunity to inform real-world clinical decision making. Combining data from other sources (e.g., meta-analyses) or enhancing EHR data with information from research studies (clinical and biomarker data) may enhance our abilities to improve the performance of clinical prediction models.
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