Inflammation as a mediator between adverse childhood experiences and adult depression: A meta-analytic structural equation model.

Exposure to adverse childhood experiences (ACEs) confers a higher risk of developing depression in adulthood, yet the mediation of inflammation remains under debate. To test this model, we conducted a systematic review and two-stage structural equation modelling meta-analysis of studies reporting correlations between ACEs before age 18, inflammatory markers and depression severity in adulthood. Scopus, Pubmed, Medline, PsycInfo, and CINAHL were searched up to 2 October 2023. Twenty-two studies reporting data on C-reactive protein (CRP, n = 12,935), interleukin-6 (IL-6, n = 4108), tumour necrosis factor-α (TNF-α, n = 2256) and composite measures of inflammation (n = 1674) were included. Unadjusted models revealed that CRP (ß = 0.003, 95 % LBCI 0.0002 to 0.0068), IL-6 (ß = 0.003, 95 % LBCI 0.001 to 0.006), and composite inflammation (ß = 0.009, 95 % LBCI 0.004 to 0.018) significantly mediated the association between ACEs and adult depression. The mediation effects no longer survived after adjusting for BMI; however, a serial mediation model revealed that BMI and IL-6 sequentially mediated the association between ACEs and depression (ß = 0.002, 95 % LBCI 0.0005 to 0.0046), accounting for 14.59 % and 9.94 % of the variance of IL-6 and depressive symptoms, respectively. Due to the cross-sectional nature of assessment of inflammation and depression findings should be approached with caution; however, results suggest that complex interactions of psychoneuroimmunological and metabolic factors underlie the association between ACEs and adulthood depression.

Disturbed sex hormone milieu in males and females with major depressive disorder and low-grade inflammation.

Sex hormones have biological effects on inflammation, and these might contribute to the sex-specific features of depression. C-reactive protein (CRP) is the most widely used inflammatory biomarker and consistent evidence shows a significant proportion (20-30 %) of patients with major depressive disorder (MDD) have CRP levels above 3 mg/L, a threshold indicating at least low-grade inflammation. Here, we investigate the interplay between sex hormones and CRP in the cross-sectional, observational Biomarkers in Depression Study. We measured serum high-sensitivity (hs-)CRP, in 64 healthy controls and 178 MDD patients, subdivided into those with hs-CRP below 3 mg/L (low-CRP; 53 males, 72 females) and with hs-CRP above 3 mg/L (high-CRP; 19 males, 34 females). We also measured interleukin-6, testosterone, 17-ß-estradiol (E2), progesterone, sex-hormone binding globulin (SHBG), follicle-stimulating and luteinising hormones, and calculated testosterone-to-E2 ratio (T/E2), free androgen and estradiol indexes (FAI, FEI), and testosterone secretion index. In males, high-CRP patients had lower testosterone than controls (p = 0.001), and lower testosterone (p = 0.013), T/E2 (p < 0.001), and higher FEI (p = 0.015) than low-CRP patients. In females, high-CRP patients showed lower SHGB levels than controls (p = 0.033) and low-CRP patients (p = 0.034). The differences in testosterone, T/E2 ratio, and FEI levels in males survived the Benjamini-Hochberg FDR correction. In linear regression analyses, testosterone (ß = -1.069 p = 0.033) predicted CRP concentrations (R2 = 0.252 p = 0.002) in male patients, and SHBG predicted CRP levels (ß = -0.628 p = 0.009, R2 = 0.172 p = 0.003) in female patients. These findings may guide future research investigating interactions between gonadal and immune systems in depression, and the potential of hormonal therapies in MDD with inflammation.

Mother-infant interaction and infant development in women at risk of postpartum psychosis with and without a postpartum relapse.

BACKGROUND: This study aimed to investigate mother-infant interaction and infant development in women at-risk of postpartum psychosis (PP), with and without a postpartum relapse. METHODS: 103 women (and their offspring) were included, 43 at-risk-of-PP because of a diagnosis of bipolar disorder, schizoaffective disorder or previous PP, and 60 with no current/previous mental illness or family history of PP. Of the at-risk women, 18 developed a psychiatric relapse within 4 weeks after delivery (AR-unwell), while 25 remained symptom-free (AR-well). Mother-infant interaction was assessed using the CARE-Index at 8 weeks' and 12 months' postpartum and infant development using the Bayley-III at 12 months' postpartum. RESULTS: Women at-risk-of-PP as a group, regardless of whether they developed a psychiatric relapse within 4 weeks after delivery, had less synchronous mother-infant interactions and had infants with less optimal cognitive, language, motor and socio-emotional development than healthy controls. In particular, boys of at-risk women had the lowest scores in cognitive, language and motor development and in mother-infant interaction, while girls of the at-risk women had the lowest scores in socio-emotional development. The synchrony in the dyad predicted infant cognitive and language development. There was no evidence for a difference in mother-infant interaction nor in infant development between the AR-unwell and AR-well groups. CONCLUSIONS: These results suggest that, while there is a lack of evidence that an early postpartum relapse in women at-risk-of-PP could represent a risk for the infant per se, maternal risk for PP may be associated with less optimal mother-infant interaction and infant development.

Effects of Pre- and Postnatal Early-Life Stress on Internalizing, Adiposity, and Their Comorbidity.

OBJECTIVE: Depression and obesity are 2 highly prevalent and often comorbid conditions. Exposure to early-life stress (ELS) has been associated with both depression and obesity in adulthood, as well as their preclinical manifestations during development. However, it remains unclear whether (1) associations differ depending on the timing of stress exposure (prenatal vs postnatal), and whether (2) ELS is a shared risk factor underlying the comorbidity between the 2 conditions. METHOD: Leveraging data from 2 large population-based birth cohorts (ALSPAC: n = 8,428 [52% male participants]; Generation R: n = 4,268 [48% male participants]), we constructed comprehensive cumulative measures of prenatal (in utero) and postnatal (from birth to 10 years) ELS. At age 13.5 years, we assessed the following: internalizing symptoms (using maternal reports); fat mass percentage (using dual-energy X-ray absorptiometry); and their comorbidity, defined as the co-occurrence of high internalizing and high adiposity. RESULTS: Both prenatal (total effect [95% CI] = 0.20 [0.16; 0.22]) and postnatal stress (ß [95%CI] = 0.22 [0.17; 0.25]) were associated with higher internalizing symptoms, with evidence of a more prominent role of postnatal stress. A weaker association (driven primarily by prenatal stress) was observed between stress and adiposity (prenatal: 0.07 [0.05; 0.09]; postnatal: 0.04 [0.01; 0.07]). Both prenatal (odds ratio [95%CI] = 1.70 [1.47; 1.97]) and postnatal (1.87 [1.61; 2.17]) stress were associated with an increased risk of developing comorbidity. CONCLUSION: We found evidence of timing and shared causal effects of ELS on psycho-cardiometabolic health in adolescence; however, future research is warranted to clarify how these associations may unfold over time. DIVERSITY & INCLUSION STATEMENT: We worked to ensure sex and gender balance in the recruitment of human participants. We worked to ensure race, ethnic, and/or other types of diversity in the recruitment of human participants. We worked to ensure that the study questionnaires were prepared in an inclusive way. One or more of the authors of this paper self-identifies as a member of one or more historically underrepresented racial and/or ethnic groups in science. One or more of the authors of this paper self-identifies as a member of one or more historically underrepresented sexual and/or gender groups in science. We actively worked to promote sex and gender balance in our author group.

Extreme deviations from the normative model reveal cortical heterogeneity and associations with negative symptom severity in first-episode psychosis from the OPTiMiSE and GAP studies.

There is currently no quantifiable method to predict long-term clinical outcomes in patients presenting with a first episode of psychosis. A major barrier to developing useful markers for this is biological heterogeneity, where many different pathological mechanisms may underly the same set of symptoms in different individuals. Normative modelling has been used to quantify this heterogeneity in established psychotic disorders by identifying regions of the cortex which are thinner than expected based on a normative healthy population range. These brain atypicalities are measured at the individual level and therefore potentially useful in a clinical setting. However, it is still unclear whether alterations in individual brain structure can be detected at the time of the first psychotic episode, and whether they are associated with subsequent clinical outcomes. We applied normative modelling of cortical thickness to a sample of first-episode psychosis patients, with the aim of quantifying heterogeneity and to use any pattern of cortical atypicality to predict symptoms and response to antipsychotic medication at timepoints from baseline up to 95 weeks (median follow-ups = 4). T1-weighted brain magnetic resonance images from the GAP and OPTiMiSE samples were processed with Freesurfer V6.0.0 yielding 148 cortical thickness features. An existing normative model of cortical thickness (n = 37,126) was adapted to integrate data from each clinical site and account for effects of gender and site. Our test sample consisted of control participants (n = 149, mean age = 26, SD = 6.7) and patient data (n = 295, mean age = 26, SD = 6.7), this sample was used for estimating deviations from the normative model and subsequent statistical analysis. For each individual, the 148 cortical thickness features were mapped to centiles of the normative distribution and converted to z-scores reflecting the distance from the population mean. Individual cortical thickness metrics of +/- 2.6 standard deviations from the mean were considered extreme deviations from the norm. We found that no more than 6.4% of psychosis patients had extreme deviations in a single brain region (regional overlap) demonstrating a high degree of heterogeneity. Mann-Whitney U tests were run on z-scores for each region and significantly lower z-scores were observed in FEP patients in the frontal, temporal, parietal and occipital lobes. Finally, linear mixed-effects modelling showed that negative deviations in cortical thickness in parietal and temporal regions at baseline are related to more severe negative symptoms over the medium-term. This study shows that even at the early stage of symptom onset normative modelling provides a framework to identify individualised cortical markers which can be used for early personalised intervention and stratification.

Electronic health records (EHRs) in clinical research and platform trials: Application of the innovative EHR-based methods developed by EU-PEARL.

OBJECTIVE: Electronic Health Record (EHR) systems are digital platforms in clinical practice used to collect patients' clinical information related to their health status and represents a useful storage of real-world data. EHRs have a potential role in research studies, in particular, in platform trials. Platform trials are innovative trial designs including multiple trial arms (conducted simultaneously and/or sequentially) on different treatments under a single master protocol. However, the use of EHRs in research comes with important challenges such as incompleteness of records and the need to translate trial eligibility criteria into interoperable queries. In this paper, we aim to review and to describe our proposed innovative methods to tackle some of the most important challenges identified. This work is part of the Innovative Medicines Initiative (IMI) EU Patient-cEntric clinicAl tRial pLatforms (EU-PEARL) project's work package 3 (WP3), whose objective is to deliver tools and guidance for EHR-based protocol feasibility assessment, clinical site selection, and patient pre-screening in platform trials, investing in the building of a data-driven clinical network framework that can execute these complex innovative designs for which feasibility assessments are critically important. METHODS: ISO standards and relevant references informed a readiness survey, producing 354 criteria with corresponding questions selected and harmonised through a 7-round scoring process (0-1) in stakeholder meetings, with 85% of consensus being the threshold of acceptance for a criterium/question. ATLAS cohort definition and Cohort Diagnostics were mainly used to create the trial feasibility eligibility (I/E) criteria as executable interoperable queries. RESULTS: The WP3/EU-PEARL group developed a readiness survey (eSurvey) for an efficient selection of clinical sites with suitable EHRs, consisting of yes-or-no questions, and a set-up of interoperable proxy queries using physicians' defined trial criteria. Both actions facilitate recruiting trial participants and alignment between study costs/timelines and data-driven recruitment potential. CONCLUSION: The eSurvey will help create an archive of clinical sites with mature EHR systems suitable to participate in clinical trials/platform trials, and the interoperable proxy queries of trial eligibility criteria will help identify the number of potential participants. Ultimately, these tools will contribute to the production of EHR-based protocol design.

Women with depression in pregnancy or a history of depression have decreased quality of mentalization in the speech to their infants.

BACKGROUND: Our study aims to understand whether depression, either in pregnancy or lifetime, affects cognitive biases (comprising the attentional focus and affective state) and mentalizing features (ability to understand children's internal mental states, thereby detecting and comprehending their behavior and intention), in maternal speech during mother-infant interaction in the first postnatal year. METHODS: We recruited 115 pregnant women (44 healthy, 46 with major depressive disorder [MDD] in pregnancy, and 25 with a history of MDD but healthy pregnancy) at 25 weeks' gestation. Three-minute videos were recorded at 8 weeks and 12 months postnatally for each dyad. Maternal speech was transcribed verbatim and coded for cognitive biases and mentalizing comments using the Parental Cognitive Attributions and Mentalization Scale (PCAMs). RESULTS: Women suffering from antenatal depression showed a decreased proportion of mentalizing comments compared with healthy women, at both 8 weeks (0.03 ± 0.01 vs. 0.07 ± 0.01, P = 0.002) and 12 months (0.02 ± 0.01 vs. 0.04 ± 0.01, P = 0.043). Moreover, compared with healthy women, both those with antenatal depression and those with a history of depression showed decreased positive affection in speech (0.13 ± 0.01 vs. 0.07 ± 0.01 and 0.08 ± 0.02, respectively P = 0.003 and P = 0.043), and made significantly fewer comments focused on their infants' experience at 8 weeks (0.67 ± 0.03 vs. 0.53 ± 0.04 and 0.49 ± 0.05, respectively P = 0.015 and P = 0.005). In linear regression models women's socioeconomic difficulties and anxiety in pregnancy contribute to these associations, while postnatal depression did not. CONCLUSIONS: Both antenatal depression and a lifetime history of depression are associated with a decreased quality of women's speech to their infants, as shown by less focus on their infant's experience, decreased positive affection, and less able to mentalize. Examining maternal speech to their infants in the early postnatal months may be particularly relevant to identify women who could benefit from strategies addressing these aspects of the interactive behavior and thus improve infant outcome in the context of depression.

Network analysis of inflammation and symptoms in recent onset schizophrenia and the influence of minocycline during a clinical trial.

Attempts to delineate an immune subtype of schizophrenia have not yet led to the clear identification of potential treatment targets. An unbiased informatic approach at the level of individual immune cytokines and symptoms may reveal organisational structures underlying heterogeneity in schizophrenia, and potential for future therapies. The aim was to determine the network and relative influence of pro- and anti-inflammatory cytokines on depressive, positive, and negative symptoms. We further aimed to determine the effect of exposure to minocycline or placebo for 6 months on cytokine-symptom network connectivity and structure. Network analysis was applied to baseline and 6-month data from the large multi-center BeneMin trial of minocycline (N = 207) in schizophrenia. Pro-inflammatory cytokines IL-6, TNF-α, and IFN-γ had the greatest influence in the inflammatory network and were associated with depressive symptoms and suspiciousness at baseline. At 6 months, the placebo group network connectivity was 57% stronger than the minocycline group, due to significantly greater influence of TNF-α, early wakening, and pathological guilt. IL-6 and its downstream impact on TNF-α, and IFN-γ, could offer novel targets for treatment if offered at the relevant phenotypic profile including those with depression. Future targeted experimental studies of immune-based therapies are now needed.

From dried bear bile to molecular investigation of differential effects of bile acids in ex vivo and in vitro models of myocardial dysfunction: Relevance for neuroinflammation.

Bile acids have been known to have both beneficial and detrimental effects on heart function, and as a consequence this can affect the brain. Inflammation is a key factor linking the heart and the brain, bile acids can reduce inflammation in the heart and, as a consequence, neuroinflammation, which may be due to the activation of different peripheral and central cellular and molecular mechanisms. Herein, we compile data published so far and summarise evidence demonstrating the effects of bile acids on myocardial cell viability and function, and its related mechanisms, in ex vivo and in vitro studies conducted in homeostatic state or in models of cardiovascular diseases. Studies show that ursodeoxycholic acid (UDCA) and tauroursodeoxycholic acid (TUDCA) do not affect the viability or contraction of cardiomyocytes in homeostatic state, and while UDCA has the capability to prevent the effect of hypoxia on reduced cell viability and beating rate, TUDCA can protect endoplasmic reticulum (ER) stress-induced apoptosis and cardiac contractile dysfunction. In contrast, deoxycholic acid (DCA) decreases contraction rate in homeostatic state, but it also prevents hypoxia-induced inflammation and oxidative stress, whereas lithocholic acid (LCA) can rescue doxazosin-induced apoptosis. Moreover, glycodeoxycholic acid (GDCA), cholic acid (CA), chenodeoxycholic acid (CDCA), glycocholic acid (GCA), taurocholic acid (TCA), taurochenodeoxycholic acid (TCDCA) and taurodeoxycholic acid (TDCA) decrease contraction, whereas CDCA decreases cell viability in homeostatic conditions. The mechanisms underlying the aforementioned contrasting effects involve a differential regulation of the TGR5, M2R and FXR receptors, as well as the cAMP signalling pathway. Overall, this review confirms the therapeutic potential of certain types of bile acids: UDCA, TUDCA, and potentially LCA, in cardiovascular diseases. By reducing inflammation in the heart, bile acids can improve heart-brain communication and promote overall health. Additional investigations are required to better elucidate mechanisms of action and more personalized clinical therapeutic doses.

Feasibility, clinical efficacy, and well-being outcomes of an online singing intervention for postnatal depression in the UK: SHAPER-PNDO, a single-arm clinical trial.

BACKGROUND: Postnatal depression (PND) affects over 12% of mothers, with numbers rising during COVID-19. Singing groups can support mothers with PND; however, online delivery has never been evaluated. SHAPER-PNDO, a single-arm clinical trial, evaluated the feasibility, clinical efficacy, and well-being outcomes of a 6-week online version of Breathe Melodies for Mums (M4M) singing intervention developed for mothers with PND during COVID-19 lockdowns. METHODS: The primary objective of this study was to assess the feasibility of a group online singing intervention for new mothers with postnatal depression. This was ascertained through recruitment rates, study retention rates, attendance rates to the singing sessions, and study completion rates. The secondary objective of the study was to assess the clinical efficacy and well-being outcomes of the singing intervention. Specifically, we measured change in Edinburgh Postnatal Depression Scale (EPDS), State-Trait Anxiety Inventory (STAI), Perceived Stress Scale (PSS), and Office for National Statistics Wellbeing Scale (ONS) scores from baseline to end-of-intervention (week 6); follow-up assessments were completed at weeks 3, 16, and 32. Mothers were eligible if they scored ≥10 on the baseline EPDS. RESULTS: Eighty-seven percent of the 37 recruited mothers completed the study, attending, on average, 5 of the 6 group singing sessions. With regard to secondary outcomes, at end-of-treatment, mothers experienced significant reductions in depression (EPDS, 16.6 ± 3.7 to 11.2 ± 5.3, 95% CI [0.79,1.65]), anxiety (STAI-S, 48.4 ± 27.1 to 41.7 ± 26.8, 95% CI [4.96, 17.65]) and stress (PSS, 29.0 ± 5.7 to 19.7 ± 5.3, 95% CI [1.33, 7.07]); and, furthermore, significant improvements in life satisfaction (ONS, 50.5 ± 23.0 to 72.8 ± 11.7, 95% CI [- 39.86, - 4.64]) and feelings of worthwhileness (ONS, 51.7 ± 30.4 to 78.6 ± 15.1, 95% CI [- 52.79, - 0.85]). Reduction on the EPDS correlated with a reduction on the BDI and the STAI-S and maternal childhood maltreatment was predictive of a smaller treatment response. CONCLUSIONS: M4M online was feasible to mothers who partook in the programme. Furthermore, M4M online supports the mental health and well-being of new mothers experiencing PND, especially when barriers to in-person treatment are present. TRIAL REGISTRATION: ClinicalTrials.gov NCT04857593 . Registered 22 April 2021, retrospectively registered.

Higher immune-related gene expression in major depression is independent of CRP levels: results from the BIODEP study.

Compelling evidence demonstrates that some individuals suffering from major depressive disorder (MDD) exhibit increased levels of inflammation. Most studies focus on inflammation-related proteins, such as serum or plasma C-reactive protein (CRP). However, the immune-related modifications associated with MDD may be not entirely captured by CRP alone. Analysing mRNA gene expression levels, we aimed to identify broader molecular immune-related phenotypes of MDD. We examined 168 individuals from the non-interventional, case-control, BIODEP study, 128 with a diagnosis of MDD and 40 healthy controls. Individuals with MDD were further divided according to serum high-sensitivity (hs)CRP levels (n = 59 with CRP <1, n = 33 with CRP 1-3 and n = 36 with CRP >3 mg/L). We isolated RNA from whole blood and performed gene expression analyses using RT-qPCR. We measured the expression of 16 immune-related candidate genes: A2M, AQP4, CCL2, CXCL12, CRP, FKBP5, IL-1-beta, IL-6, ISG15, MIF, GR, P2RX7, SGK1, STAT1, TNF-alpha and USP18. Nine of the 16 candidate genes were differentially expressed in MDD cases vs. controls, with no differences between CRP-based groups. Only CRP mRNA was clearly associated with serum CRP. In contrast, plasma (proteins) IL-6, IL-7, IL-8, IL-10, IL-12/IL-23p40, IL-16, IL-17A, IFN-gamma and TNF-alpha, and neutrophils counts, were all differentially regulated between CRP-based groups (higher in CRP >3 vs. CRP <1 and/or controls), reflecting the gradient of CRP values. Secondary analyses on MDD individuals and controls with CRP values <1 mg/L (usually interpreted as 'no inflammation') confirmed MDD cases still had significantly different mRNA expression of immune-related genes compared with controls. These findings corroborate an immune-related molecular activation in MDD, which appears to be independent of serum CRP levels. Additional biological mechanisms may then be required to translate this mRNA signature into inflammation at protein and cellular levels. Understanding these mechanisms will help to uncover the true immune abnormalities in depression, opening new paths for diagnosis and treatment.

Comparative efficacy of psychological interventions on immune biomarkers: A systematic review and network meta-analysis (NMA).

Psychological interventions are viable, cost-effective strategies for improving clinical and psychological impact of inflammation-related conditions. However, their efficacy on immune system function remains controversial. We performed a systematic review and frequentist random-effects network meta-analysis of randomised controlled trials (RCTs) assessing the effects of psychological interventions, against a control condition, on biomarkers of innate and adaptive immunity in adults. PubMed, Scopus, PsycInfo, and Web of Science were searched from inception up to Oct 17, 2022. Cohen's d at 95% confidence interval (CI) was calculated to assess the effect sizes of each class of intervention against active control conditions at post-treatment. The study was registered in PROSPERO (CRD42022325508). Of the 5024 articles retrieved, we included 104 RCTs reporting on 7820 participants. Analyses were based on 13 types of clinical interventions. Compared with the control conditions, cognitive therapy (d =  - 0.95, 95% CI: -1.64 to - 0.27), lifestyle (d =  - 0.51, 95% CI: -0.99 to - 0.02), and mindfulness-based (d =  - 0.38, 95% CI: -0.66 to - 0.09) interventions were associated with post-treatment reduction of proinflammatory cytokines and markers. Mindfulness-based interventions were also significantly associated with post-treatment increase in anti-inflammatory cytokines (d = 0.69, 95% CI: 0.09 to 1.30), while cognitive therapy was associated also with post-treatment increase in white blood cell count (d = 1.89, 95% CI: 0.05 to 3.74). Results on natural killer cells activity were non-significant. Grade of evidence was moderate for mindfulness and low-to-moderate for cognitive therapy and lifestyle interventions; however, substantial overall heterogeneity was detected in most of the analyses.

The interaction between kynurenine pathway, suicidal ideation and augmentation therapy with minocycline in patients with treatment-resistant depression.

BACKGROUND AND AIMS: We investigated kynurenine pathway (KP) metabolites levels and their association with suicidal ideation in patients with treatment-resistant depression (TRD) and elevated peripheral inflammation. The effect of antidepressant augmentation with minocycline on KP metabolites was tested. METHODS: We analysed data from MINocycline in DEPression, a 4-week, randomized, placebo controlled (1:1) trial of minocycline added to antidepressant treatment in 39 TRD patients (n = 18 minocycline; n = 21 placebo) with C-reactive protein (CRP) ⩾1 mg/L. At baseline and at week 4, we collected data on suicidality (Beck Depression Inventory) and blood samples to measure inflammatory markers and KP metabolites. We tested (1) the association of KP metabolites ratios with inflammatory markers and suicidal ideation at baseline and (2) the role of suicidality and treatment (minocycline vs placebo) in affecting KP changes over time. RESULTS: At baseline, kynurenine/tryptophan (KYN/TRP) ratio positively correlated with high-sensitivity CRP (Spearman's ρ = 0.35, p = 0.02) and IL-10, (ρ = 0.41, p = 0.009); and tumour necrosis factor was positively correlated with quinolinic acid/3-hydroxykynurenine ratio (ρ = 0.55, p < 0.001). Moreover, participants with suicidal ideation showed higher levels of KYN/TRP (U = 143.000, p = 0.02) than those without suicidal ideation. There was no significant effect of minocycline on KP metabolites changes from baseline to week 4. However, in the minocycline group, the number of participants with suicidal thoughts decreased from 44.4% (8/18) to 22.2% (4/18). CONCLUSION: Increased KP neurotoxic metabolites are associated with elevated peripheral inflammation in depressed individuals, particularly in those with suicidal ideation. Targeting KP in this population could be a potential effective personalized approach. Whether this includes minocycline should be investigated in future larger trials.

Sickness behaviour and depression: An updated model of peripheral-central immunity interactions.

Current research into mood disorders indicates that circulating immune mediators participating in the pathophysiology of chronic somatic disorders have potent influences on brain function. This paradigm has brought to the fore the use of anti-inflammatory therapies as adjunctive to standard antidepressant therapy to improve treatment efficacy, particularly in subjects that do not respond to standard medication. Such new practice requires biomarkers to tailor these new therapies to those most likely to benefit but also validated mechanisms of action describing the interaction between peripheral immunity and brain function to optimize target intervention. These mechanisms are generally studied in preclinical models that try to recapitulate the human disease, MDD, through peripherally induced sickness behaviour. In this proposal paper, after an appraisal of the data in rodent models and their adherence to the data in clinical cohorts, we put forward a modified model of periphery-brain interactions that goes beyond the currently established view of microglia cells as the drivers of depression. Instead, we suggest that, for most patients with mild levels of peripheral inflammation, brain barriers are the primary actors in the pathophysiology of the disease and in treatment resistance. We then highlight data gaps in this proposal and suggest novel lines of research.

Emotional, inflammatory, and genetic factors of resilience and vulnerability to depression in patients with premenopausal breast cancer: A longitudinal study protocol.

BACKGROUND: Psychosocial stress and depressive disorder have been associated with cancer as putative contributors to worse prognosis. On the other hand, cancer diagnosis is a recognised life event that can contribute to distress and depressive states. Humoral and cellular inflammation can promote depressive disorder by means of decreased monoamine synthesis, glutamate neurotoxicity, neurogenesis and neuroplasticity, dysregulated hypothalamic-pituitary-adrenal axis, and glucocorticoid resistance. This protocol objectives are to observe the interactions between psychosocial variables and biochemical and immunological biomarkers in a longitudinal, prospective design; to identify inflammation-related depression endophenotypes in breast cancer patients and to understand if early diagnosed and treated depression in this population will translate in better inflammation status and better global prognosis. METHODS: Prospective observational cohort, composed by 100 consecutive premenopausal patients, diagnosed with non-distant metastatic breast carcinoma and with no history of major psychopathology or other organic illness. The participants will have an in-person assessment in three different moments, along illness treatment and follow-up, with respect to cytometric, immunologic, and psychosocial parameters and will be tested for depression vulnerability and resilience inflammation-related functional genetic polymorphisms. Additionally, at years 5 and 10 post enrollment, patients`medical records will be assessed. As a control cohort, all patients excluded due to psychiatric history or past psychiatric treatments will have their clinical records assessed at years 5 and 10 after admission. All the data will be managed with the SPSS® software. DISCUSSION AND CONCLUSION: This study is an original longitudinal cohort of breast cancer premenopausal patients, with a comprehensive approach to psychosocial, clinical, inflammatory, and genetic variables. It expects to provide evidence regarding the links between genetic, cytometric, immunologic, and psychosocial factors, their potential contribution to the pathophysiology of depressive disorder, breast cancer course, progression, and prognosis. It may further contribute with data to better efficacy of the psycho-oncological interventions. TRIAL REGISTRATION: National Commission of Data Protection (CNPD) 13413/2017; Ethics Committee of IPOP project code CI-IPOP81/2017.

Cognitive function in early-phase schizophrenia-spectrum disorder: IQ subtypes, brain volume and immune markers.

BACKGROUND: Evidence suggests that cognitive subtypes exist in schizophrenia that may reflect different neurobiological trajectories. We aimed to identify whether IQ-derived cognitive subtypes are present in early-phase schizophrenia-spectrum disorder and examine their relationship with brain structure and markers of neuroinflammation. METHOD: 161 patients with recent-onset schizophrenia spectrum disorder (<5 years) were recruited. Estimated premorbid and current IQ were calculated using the Wechsler Test of Adult Reading and a 4-subtest WAIS-III. Cognitive subtypes were identified with k-means clustering. Freesurfer was used to analyse 3.0 T MRI. Blood samples were analysed for hs-CRP, IL-1RA, IL-6 and TNF-α. RESULTS: Three subtypes were identified indicating preserved (PIQ), deteriorated (DIQ) and compromised (CIQ) IQ. Absolute total brain volume was significantly smaller in CIQ compared to PIQ and DIQ, and intracranial volume was smaller in CIQ than PIQ (F(2, 124) = 6.407, p = 0.002) indicative of premorbid smaller brain size in the CIQ group. CIQ had higher levels of hs-CRP than PIQ (F(2, 131) = 5.01, p = 0.008). PIQ showed differentially impaired processing speed and verbal learning compared to IQ-matched healthy controls. CONCLUSIONS: The findings add validity of a neurodevelopmental subtype of schizophrenia identified by comparing estimated premorbid and current IQ and characterised by smaller premorbid brain volume and higher measures of low-grade inflammation (CRP).

Sex differences in a double-blind randomized clinical trial with minocycline in treatment-resistant depressed patients: CRP and IL-6 as sex-specific predictors of treatment response.

Background: Inflammation is a well-known risk factor for depression. Specifically, patients who do not respond to antidepressant treatment show higher levels of inflammatory biomarkers compared with responders. Thus, several studies have investigated the efficacy of anti-inflammatory add-on treatment in this population. However, major depressive disorder is more prevalent in females than in males, with sex differences present in antidepressant treatment response and in immune system regulation. To explore sex differences in inflammatory profiles and treatment responses, we investigated a cohort of patients with treatment resistant depression (TRD), for which they received an adjunctive, anti-inflammatory treatment with minocycline - the Minocycline in Depression (MINDEP) study. Methods: The MINDEP study is a 4-week double-blind, randomised, placebo-controlled clinical trial (stratified by sex) with 39 TRD participants, which demonstrated the efficacy of minocycline, an antibiotic with anti-inflammatory properties, in TRD patients with major depressive disorder (MDD) and evidence of low-grade inflammation measured with C-reactive protein (CRP) ≥ 3 mg/L. In these secondary analyses, we investigated the differential effects of minocycline in females (N = 22, 10 randomised to minocycline and 12 randomised to placebo) and in males (N = 17, 8 randomised to minocycline and 9 randomised to placebo) on changes in depressive symptoms (Δ- Hamilton Rating Scale for Depression (HAMD)-17), taking also into consideration CRP levels (CRP ≥3 mg/L vs. CRP <3 mg/L). Additionally, we investigated the role of serum IL-6 in predicting treatment response to minocycline, using sex-specific medians of IL-6, in novel exploratory analyses. Results: Sex differences in Δ-HAMD-17 indicate that only females (F = 10.49, p = 0.005), but not males (F = 1.64, p = 0.22), presented an effect of CRP levels on the response to minocycline. Also, we detected sex differences in the relationship between serum CRP and IL-6 levels: CRP was strongly correlated with IL-6 in females (Spearman's ρ = 0.658, P < 0.001) but not in males (ρ = 0.007, p = 0.979). Exploratory analyses found that IL-6 was indeed a better predictor of response than minocycline than CRP, as we found an interaction between study arms and IL-6 groups (above and below the IL-6 sex-specific median) in females (F = 4.435 p = 0.050) and, at trend statistical level, in males (F = 4.258 p = 0.060). Moreover, Δ-HAMD-17 was numerically comparable in the two high-IL-6 group taking minocycline (females, mean 9.20 ± SD 7.80; males, mean 8.80 ± SD 5.97), confirming that high IL-6, differently from high CRP, identified responders to minocycline both in males and females. Conclusion: Our findings highlight the need of sex-specific inflammatory biomarkers in predicting antidepressant response to anti-inflammatories in TRD patients, with the possibility of CRP being a relevant predictor of treatment response only for females, and IL-6 being relevant for both sexes.

A Protocol to Understand the Implementation and Experiences of an Online Community-Based Performance Arts Programme Through and Beyond the COVID-19 Pandemic, Brain Waves.

Introduction: Individuals living with acquired brain injury experience numerous psychological, physical, and social challenges. Since the COVID-19 pandemic, many have experienced additional isolation, mental health issues and have had limited access to social and physical activities otherwise available in the community. Materials and Methods: Brain Waves is a 12-week online performance arts programme developed during the COVID-19 pandemic, for people with acquired brain injury (ABI). The research component of Brain Waves is a qualitative study, using Interpretative Phenomenological Analysis (IPA) and ethnographic methods (Observations and Interviews). The study will recruit two distinct populations: individuals living with acquired brain injury (including people who have experienced traumatic brain injury and stroke who are participating in the programme) and stakeholders (facilitators, involved in the delivery of Brain Waves). This paper presents the protocol for a project which aims to gain an understanding of the implementation and experiences of creating and participating in an online community-based performance arts programme.

Neurogenesis is disrupted in human hippocampal progenitor cells upon exposure to serum samples from hospitalized COVID-19 patients with neurological symptoms.

Coronavirus disease 2019 (COVID-19), represents an enormous new threat to our healthcare system and particularly to the health of older adults. Although the respiratory symptoms of COVID-19 are well recognized, the neurological manifestations, and their underlying cellular and molecular mechanisms, have not been extensively studied yet. Our study is the first one to test the direct effect of serum from hospitalised COVID-19 patients on human hippocampal neurogenesis using a unique in vitro experimental assay with human hippocampal progenitor cells (HPC0A07/03 C). We identify the different molecular pathways activated by serum from COVID-19 patients with and without neurological symptoms (i.e., delirium), and their effects on neuronal proliferation, neurogenesis, and apoptosis. We collected serum sample twice, at time of hospital admission and approximately 5 days after hospitalization. We found that treatment with serum samples from COVID-19 patients with delirium (n = 18) decreased cell proliferation and neurogenesis, and increases apoptosis, when compared with serum samples of sex- and age-matched COVID-19 patients without delirium (n = 18). This effect was due to a higher concentration of interleukin 6 (IL6) in serum samples of patients with delirium (mean ± SD: 229.9 ± 79.1 pg/ml, vs. 32.5 ± 9.5 pg/ml in patients without delirium). Indeed, treatment of cells with an antibody against IL6 prevented the decreased cell proliferation and neurogenesis and the increased apoptosis. Moreover, increased concentration of IL6 in serum samples from delirium patients stimulated the hippocampal cells to produce IL12 and IL13, and treatment with an antibody against IL12 or IL13 also prevented the decreased cell proliferation and neurogenesis, and the increased apoptosis. Interestingly, treatment with the compounds commonly administered to acute COVID-19 patients (the Janus kinase inhibitors, baricitinib, ruxolitinib and tofacitinib) were able to restore normal cell viability, proliferation and neurogenesis by targeting the effects of IL12 and IL13. Overall, our results show that serum from COVID-19 patients with delirium can negatively affect hippocampal-dependent neurogenic processes, and that this effect is mediated by IL6-induced production of the downstream inflammatory cytokines IL12 and IL13, which are ultimately responsible for the detrimental cellular outcomes.

Birth of the blues: emotional sound processing in infants exposed to prenatal maternal depression.

BACKGROUND: Offspring exposed to prenatal maternal depression (PMD) are vulnerable to depression across their lifespan. The underlying cause(s) for this elevated intergenerational risk is most likely complex. However, depression is underpinned by a dysfunctional frontal-limbic network, associated with core information processing biases (e.g. attending more to sad stimuli). Aberrations in this network might mediate transmission of this vulnerability in infants exposed to PMD. In this study, we aimed to explore the association between foetal exposure to PMD and frontal-limbic network function in infancy, hypothesising that, in response to emotional sounds, infants exposed to PMD would exhibit atypical activity in these regions, relative to those not exposed to PMD. METHOD: We employed a novel functional magnetic resonance imaging sequence to compare brain function, whilst listening to emotional sounds, in 78 full-term infants (3-6 months of age) born to mothers with and without a diagnosis of PMD. RESULTS: After exclusion of 19 datasets due to infants waking up, or moving excessively, we report between-group brain activity differences, between 29 infants exposed to PMD and 29 infants not exposed to PMD, occurring in temporal, striatal, amygdala/parahippocampal and frontal regions (p < 0.005). The offspring exposed to PMD exhibited a relative increase in activation to sad sounds and reduced (or unchanged) activation to happy sounds in frontal-limbic clusters. CONCLUSIONS: Findings of a differential response to positive and negative valanced sounds by 3-6 months of age may have significant implications for our understanding of neural mechanisms that underpin the increased risk for later-life depression in this population.