Publications by authors named "Carmine M Pariante"

263 Publications

Inflammation and early life stress: An updated review of childhood trauma and inflammatory markers in adulthood.

Pharmacol Biochem Behav 2021 Oct 22:173291. Epub 2021 Oct 22.

Stress, Psychiatry and Immunology Lab, Institute of Psychiatry, Psychology and Neuroscience, King's College London, Maurice Wohl Clinical Neuroscience Institute, Cutcombe Road, London, SE5 9RT, United Kingdom of Great Britain and Northern Ireland. Electronic address:

Inflammation as a neurobiological consequence of childhood trauma has frequently been reported across research, however recent investigations suggest this relationship may be dependent on specificities such as type of trauma, type of inflammatory marker and additional mediatory variables - such as body mass index (BMI), age and sex. As an updated version of a previous review by Baumeister et al., the current review comprised a search of PubMed, which identified 37 articles that collectively assessed 4 inflammatory markers (CRP, IL-6, TNFα and IL-1β.) Review of the studies revealed predominantly non-significant associations between childhood trauma and elevated levels of all inflammatory markers in adulthood. However, in line with previous research, discrepancies in significance arose when considering type of trauma, type of inflammatory marker and additional variables. Compared to neglect, abuse showed more significant associations with elevated inflammatory markers in adulthood, though significance for abuse was dependent on the individual subtypes (emotional, physical or sexual). Mediation analyses reported BMI as a significant mediator, though, when controlled for, no significant differences were found. Sex differences were reported but investigations were sparse. Future research should investigate the mediatory role of sex differences in the inflammatory effects of childhood trauma. Many studies in the review were restricted by use of the same trauma measure - the Childhood Trauma Questionnaire. To assess greater variety of trauma types, future studies should utilise other standardized measures to explore these avenues.
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http://dx.doi.org/10.1016/j.pbb.2021.173291DOI Listing
October 2021

Relationship between CRP and depression: a genetically sensitive study in Sri Lanka.

J Affect Disord 2021 Oct 12. Epub 2021 Oct 12.

Social Genetic and Developmental Research Centre, Institute of Psychiatry, Psychology & Neuroscience, King's College London, UK.

Background: Previous studies have shown associations between major depression and C-reactive protein (CRP) levels. Few studies have considered the extent to which shared genetic and environmental factors contribute to this association, nor have they considered the relationship outside of European populations. We examined the association between CRP levels and depression and their aetiology in a Sri Lankan population.

Methods: Data were collected from 2577 twins and 899 singletons in Colombo, Sri Lanka. Depression symptoms were assessed using the revised Beck Depression Inventory (BDI-II). High-sensitive CRP blood levels were assessed using immunoturbidimetry. Linear regressions were performed to test the association between CRP and depression. The heritability of CRP levels was estimated using Structural Equation Modelling.

Results: CRP was significantly associated with BMI (p<0.01) but not depression (p>0.05). In males, variance in CRP levels was explained by shared environment (51% 95%CIs: 13-62) and non-shared environment (45% 95%CIs: 36-54). In contrast, in females, CRP variance was explained by genetic (41% 95%CIs: 10-52) and non-shared environment (56% 95%CIs: 47-67). A genetic correlation between CRP and BMI was observed in females only.

Limitations: CRP level was based on a single data collection point, longer term data collection would give a more accurate picture of an individual's state of inflammation.

Conclusions: The lack of association between depression and CRP strengthens the hypothesis that inflammation might contribute to the development of some, but not all types of depression. CRP levels were moderated by the environment, suggesting interventions aimed at reducing CRP levels and risk for inflammatory conditions, particularly in males.
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http://dx.doi.org/10.1016/j.jad.2021.10.003DOI Listing
October 2021

Increased maternal inflammation and poorer infant neurobehavioural competencies in women with a history of major depressive disorder from the psychiatry research and motherhood - Depression (PRAM-D) study.

Brain Behav Immun 2021 Oct 10;99:223-230. Epub 2021 Oct 10.

King's College London, Institute of Psychiatry, Psychology and Neuroscience, Department of Psychological Medicine, London SE5 9RT, UK. Electronic address:

Introduction: Stress in pregnancy is associated with adverse outcomes in offspring, and developmental programming is a potential mechanism. We have previously shown that depression in pregnancy is a valid and clearly defined stress paradigm, and both maternal antenatal and offspring stress-related biology is affected. This study aims to clarify whether maternal biology in pregnancy and offspring outcomes can also be influenced by a history of a prior depression, in the absence of depression in pregnancy. Our primary hypothesis is that, similarly to women with depression in pregnancy, women with a history of depression but who are not depressed in pregnancy will have increased cortisol secretion and markers of immune system function, and that their offspring will have poorer neuro-developmental competencies and increased cortisol stress response.

Methods: A prospective longitudinal design was used in 59 healthy controls and 25 women with a past history of depression who were not depressed in pregnancy, named as 'history-only', and their offspring. Maternal antenatal stress-related biology (cortisol and markers of immune system function) and offspring outcomes (gestational age at birth, neonatal neurobehaviour (Neonatal Behavioural Assessment Scale, NBAS), cortisol stress response and basal cortisol at 2 and 12 months) and cognitive, language and motor development (Bayley Scales of Infant and Toddler Development (BSID)) were measured.

Results: Compared with healthy pregnant women, those with a history of depression who remain free of depression in pregnancy exhibit increased markers of immune system function in pregnancy: IL-8 (d = 0.63, p = 0.030), VEGF (d = 0.40, p = 0.008) and MCP-1 (d = 0.61, p = 0.002) and have neonates with lower neurobehavioural scores in most areas, reaching statistical significance in thesocial-interactive (d = 1.26, p = 0.015) cluster. However, there were no differences in maternal or offspring HPA axis function or in infant development at 12 months.

Conclusion: Our study indicates that pregnant women with a history of depression have increased markers of immune system function, and their offspring show behavioural alterations that may be the effects of in utero programming, epigenetic factors or genetic predisposition.
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http://dx.doi.org/10.1016/j.bbi.2021.09.020DOI Listing
October 2021

From dried bear bile to molecular investigation: A systematic review of the effect of bile acids on cell apoptosis, oxidative stress and inflammation in the brain, across pre-clinical models of neurological, neurodegenerative and neuropsychiatric disorders.

Brain Behav Immun 2021 Sep 30;99:132-146. Epub 2021 Sep 30.

Stress, Psychiatry and Immunology Laboratory, Department of Psychological Medicine, Institute of Psychiatry, Psychology & Neuroscience, King's College London, UK. Electronic address:

Bile acids, mainly ursodeoxycholic acid (UDCA) and its conjugated species glycoursodeoxycholic acid (GUDCA) and tauroursodeoxycholic acid (TUDCA) have long been known to have anti-apoptotic, anti-oxidant and anti-inflammatory properties. Due to their beneficial actions, recent studies have started to investigate the effect of UDCA, GUDCA, TUDCA on the same mechanisms in pre-clinical models of neurological, neurodegenerative and neuropsychiatric disorders, where increased cell apoptosis, oxidative stress and inflammation in the brain are often observed. A total of thirty-five pre-clinical studies were identified through PubMed/Medline, Web of Science, Embase, PsychInfo, and CINAHL databases, investigating the role of the UDCA, GUDCA and TUDCA in the regulation of brain apoptosis, oxidative stress and inflammation, in pre-clinical models of neurological, neurodegenerative and neuropsychiatric disorders. Findings show that UDCA reduces apoptosis, reactive oxygen species (ROS) and tumour necrosis factor (TNF)-α production in neurodegenerative models, and reduces nitric oxide (NO) and interleukin (IL)-1β production in neuropsychiatric models; GUDCA decreases lactate dehydrogenase, TNF-α and IL-1β production in neurological models, and also reduces cytochrome c peroxidase production in neurodegenerative models; TUDCA decreases apoptosis in neurological models, reduces ROS and IL-1β production in neurodegenerative models, and decreases apoptosis and TNF-α production, and increases glutathione production in neuropsychiatric models. In addition, findings suggest that all the three bile acids would be equally beneficial in models of Huntington's disease, whereas UDCA and TUDCA would be more beneficial in models of Parkinson's disease and Alzheimer's disease, while GUDCA in models of bilirubin encephalopathy and TUDCA in models of depression. Overall, this review confirms the therapeutic potential of UDCA, GUDCA and TUDCA in neurological, neurodegenerative and neuropsychiatric disorders, proposing bile acids as potential alternative therapeutic approaches for patients suffering from these disorders.
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http://dx.doi.org/10.1016/j.bbi.2021.09.021DOI Listing
September 2021

The role of AQP4 in the pathogenesis of depression, and possible related mechanisms.

Brain Behav Immun 2021 Nov 30;98:366-377. Epub 2021 Aug 30.

Stress, Psychiatry and Immunology Laboratory, Department of Psychological Medicine, Institute of Psychiatry, Psychology & Neuroscience, King's College London, UK. Electronic address:

Modulation of the aquaporin 4 (AQP4) water-regulatory channel or production of autoantibodies against this protein have been implicated in a variety of neuropsychiatric conditions, and possible mechanisms have been proposed. However, the nature of the interaction between AQP4 expression and its implications in depression remain elusive. To our knowledge, this is the first review summarising data for the involvement of AQP4 in the context of depression and related mechanisms across a wide range of experimental studies: pre-clinical (KO and wild-type), post-mortem, ex vivo, and clinical studies in depression. Overall, preclinical AQP4 wild-type studies showed that exposure to stress or inflammation, used as models of depression, decreased AQP4 protein and gene expression in various brain regions, including prefrontal cortex (PFC), choroid plexus and, especially, hippocampus. In preclinical AQP4 KO studies, AQP4 expression is necessary to prevent the effect of stress and inflammation on reduced neurogenesis and gliogenesis, and increased apoptosis and depressive-like behaviours. While in post-mortem and ex vivo studies of depression AQP4 expression was usually decreased in the hippocampus, prefrontal cortex and locus coeruleus, in clinical studies, where mRNA AQP4 expression or serum AQP4 autoantibodies were measured, there were no differences in depressed patients when compared with controls. In the future, studies should further investigate the mechanisms underlying the action of AQP4, and continue exploring if AQP4 autoantibodies are either contributing or underlying mechanisms of depression, or whether they are simply a mechanism underlying other autoimmune conditions where depression is present.
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http://dx.doi.org/10.1016/j.bbi.2021.08.232DOI Listing
November 2021

Dysconnectivity of a brain functional network was associated with blood inflammatory markers in depression.

Brain Behav Immun 2021 Nov 25;98:299-309. Epub 2021 Aug 25.

Brain Mapping Unit, Department of Psychiatry, University of Cambridge, Cambridge, UK.

Objective: There is increasing evidence for a subgroup of major depressive disorder (MDD) associated with heightened peripheral blood inflammatory markers. In this study, we aimed to understand the mechanistic brain-immune axis in inflammation-linked depression by investigating associations between functional connectivity (FC) of brain networks and peripheral blood immune markers in depression.

Methods: Resting-state functional magnetic resonance imaging (fMRI) and peripheral blood inflammatory markers (C-reactive protein; CRP, interleukin-6; IL-6 and immune cells) were collected on N = 46 healthy controls (HC; CRP ≤ 3 mg/L) and N = 83 cases of depression, stratified further into low CRP cases (loCRP cases; ≤ 3 mg/L; N = 50) and high CRP cases (hiCRP cases; > 3 mg/L; N = 33). In a two-part analysis, network-based statistics (NBS) was firstly used to ascertain whole-brain FC differences in HC vs hiCRP cases. Secondly, we investigated the association between this network of interconnected brain regions and continuous measures of peripheral CRP (N = 83), IL-6 (N = 72), neutrophils and CD4 T-cells (N = 36) in depression cases only.

Results: Case-control NBS testing revealed a single network of abnormally attenuated FC in the high CRP depression cases compared to healthy controls. Connections within this network were mainly between brain regions located in the left insula/frontal operculum and posterior cingulate cortex, which were assigned to ventral attention and default mode canonical fMRI networks respectively. Within-group analysis across all depression cases, secondarily demonstrated that FC within the identified network significantly negatively scaled with CRP, IL-6 and neutrophils.

Conclusions: The findings suggest that inflammation is associated with disruption of functional connectivity within a brain network deemed critical for interoceptive signalling, e.g. accurate communication of peripheral bodily signals such as immune states to the brain, with implications for the pathogenesis of inflammation-linked depression.
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http://dx.doi.org/10.1016/j.bbi.2021.08.226DOI Listing
November 2021

Cortisol and inflammatory biomarker levels in youths with attention deficit hyperactivity disorder (ADHD): evidence from a systematic review with meta-analysis.

Transl Psychiatry 2021 08 19;11(1):430. Epub 2021 Aug 19.

Department of Psychological Medicine, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.

Several studies reported abnormal cortisol and inflammatory biomarker levels in youths with attention deficit hyperactivity disorder (ADHD), but the results have not been conclusive. We conducted a systematic review followed by a meta-analysis of case-control studies assessing blood or saliva cortisol levels and blood levels of inflammatory biomarkers in youth with ADHD. The effect sizes (ES) were synthesized by using a random-effects model. In the 19 studies on cortisol levels (totaling n = 916 youth with ADHD and n = 947 typically developing (TD), healthy youth), youth with ADHD have lower basal cortisol levels at any time-points during the day (effect size: .68; p = 0.004) and lower cumulative levels of cortisol (ES: .39, p = .008) throughout the day than TD youth. Moreover, morning cortisol levels were lower in ADHD youth when compared with TD youth (14 studies, n = 1679, ES: .84, p = 0.003), while there is no difference for the afternoon cortisol levels (p = 0.48). The meta-analysis on inflammation biomarker was conducted on 4 studies (totaling n = 404 youth) showed that Tumour Necrosis Factor-alpha (TNF-α) was lower in ADHD when compared with TD (3 studies, n = 257 youth, p = 0.004), while no differences for Interleukin-1β(IL-1β) (p = 0.21), IL-6 (p = 0.09) and IL-10 (p = 0.77). The lower cortisol in the context of low TNF-α levels may indicate a specific pattern of biomarkers in ADHD, and further investigation is warranted.
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http://dx.doi.org/10.1038/s41398-021-01550-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8377148PMC
August 2021

Neurogenic and anti-inflammatory effects of probiotics in Parkinson's disease: A systematic review of preclinical and clinical evidence.

Brain Behav Immun 2021 Nov 5;98:59-73. Epub 2021 Aug 5.

National Institute for Health Research (NIHR), Mental Health Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King's College, London, UK. Electronic address:

There is increasing evidence highlighting the potential role of the gut-brain axis in the pathogenesis of Parkinson's disease (PD) and on the use of probiotics as a therapeutic strategy for this neurodegenerative disorder. While several studies have been published on the topic in recent years, there is still a lack of a comprehensive understanding of the effects of probiotics in PD and their possible underlying mechanisms. Through this systematic review, we collected a total of 17 articles, consisting of preclinical and clinical models of PD investigating the effect of probiotics on (1) energy metabolism, (2) inflammation and oxidative stress, (3) neurodegeneration, as well as (4) motor and (5) non-motor function. Articles were obtained from PubMed/Medline, Scopus, Web of Science and Embase databases. Findings from preclinical studies suggest that treatment with probiotics increases glucose metabolism (increased secretion of glucagon-like peptide-1), reduces peripheral and central inflammation (reduced interleukin-6 and tumor necrosis factor-α (TNF-α)), reduces peripheral and central oxidative stress (reduced peripheral superoxide anion levels and increased central antioxidant glutathione levels), decreases neurodegeneration (increased numbers of tyrosine hydroxylase dopaminergic neurons and levels of brain-derived neurotrophic factor), increases motor function (increased motor agility) and non-motor function (decreased memory deficits). Similarly, findings from clinical studies suggest that probiotics increase glucose metabolism (reduced insulin resistance), reduce peripheral inflammation (reduced peripheral TNF-α expression and C-reactive protein levels), and increase motor and non-motor function (decreased overall PD symptomatology and constipation); however, findings on oxidative stress were inconclusive across studies. Overall, this review is the first one to systematically report evidence for the putative beneficial effects of probiotics on molecular and cellular mechanisms, as well as behavioural phenotypes, in either preclinical or clinical studies in PD. However, additional and more robust studies are still needed to confirm these outcomes, and should aim to focus more on bench-to-bedside approaches, in order to address the existing gaps between preclinical and clinical findings in this field.
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http://dx.doi.org/10.1016/j.bbi.2021.07.026DOI Listing
November 2021

Peripheral levels of C-reactive protein, tumor necrosis factor-α, interleukin-6, and interleukin-1β across the mood spectrum in bipolar disorder: A meta-analysis of mean differences and variability.

Brain Behav Immun 2021 10 28;97:193-203. Epub 2021 Jul 28.

Deakin University, IMPACT - the Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Barwon Health, 75 Pigdon's Road, Waurn Ponds, Geelong, VIC 3216, Australia. Electronic address:

Importance: 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.

Objective: 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.

Data Sources: Systematic review of observational studies in PubMed and PsycInfo up to February 2nd, 2020.

Study Selection: Case-control studies reporting inflammatory mediators' levels in BD and controls.

Data Extraction And Synthesis: 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).

Main Outcomes And Measures: 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.

Results: 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.

Conclusions And Relevance: 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.
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http://dx.doi.org/10.1016/j.bbi.2021.07.014DOI Listing
October 2021

Maternal perceived bonding towards the infant and parenting stress in women at risk of postpartum psychosis with and without a postpartum relapse.

J Affect Disord 2021 Nov 5;294:210-219. Epub 2021 Jun 5.

Department of Psychological Medicine, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, SE5 9RX, UK; National Institute for Health Research (NIHR) Mental Health Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King's College London, London, UK.

Background: Postpartum psychosis (PP) is the most severe psychiatric disorder associated with childbirth. However, there is little research on maternal bonding towards the infant and parenting stress in this clinical population.

Methods: We investigated maternal bonding during pregnancy and post-partum in 75 women: 46 at risk of PP (AR), because of a DSM-IV diagnosis of bipolar disorder, schizoaffective disorder or previous PP, and 29 healthy controls. Of the AR women, 19 developed a psychiatric relapse within 4 weeks' post-partum (AR-unwell), while 27 remained symptom-free (AR-well). We investigated childhood maltreatment, parenting stress and psychiatric symptoms as potential predictors of maternal bonding.

Results: In pregnancy, AR-unwell women reported a more negative affective experience towards their infants than AR-well women (d = 0.87, p = .001), while postnatally there was no significant difference in bonding. In contrast, AR women as a group reported a more negative affective experience than HC postnatally (d = 0.69, p = .002; d = 0.70, p = .010), but not antenatally. Parenting stress and psychiatric symptoms significantly predicted less optimal postnatal bonding (b = -0.10, t = -4.29, p < .001; b = -0.37, t = -4.85, p < .001) but only psychiatric symptoms explained the difference in bonding between AR and HC (b = -1.18, 95% BCa CI [-2.70,-0.04]).

Limitations: A relatively small sample size precluded a more in-depth investigation of underlying pathways.

Conclusion: This study provides new information on maternal bonding in women at risk of PP, and particularly in those that do and do not develop a postpartum relapse. The results suggest that improving maternal symptoms and parenting stress in the perinatal period in women at risk of PP could also have positive effects on bonding.
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http://dx.doi.org/10.1016/j.jad.2021.05.076DOI Listing
November 2021

What can neuroimmunology teach us about the symptoms of long-COVID?

Oxf Open Immunol 2021 10;2(1):iqab004. Epub 2021 Feb 10.

Department of Psychological Medicine, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.

Long-Coronavirus Disease (Long-COVID) is becoming increasingly recognized due to the persistence of symptoms such as profound fatigue, neurocognitive difficulties, muscle pains and weaknesses and depression, which would last beyond 3-12 weeks following infection with SARS-CoV-2. These particular symptoms have been extensively observed and studied in the context of previous psychoneuroimmunology research. In this short commentary, we discuss how previous neuroimmunology studies could help us to better understand pathways behind the development of these prolonged symptoms. Various mechanisms, including viral neuroinvasion, glial cells activation, neurogenesis, oxidative stress have been shown to explain these symptoms in the context of other disorders. Previous neuroimmunology findings could represent helpful pointers for future research on long-COVID symptoms and suggest potential management strategies for patients suffering with long-COVID.
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http://dx.doi.org/10.1093/oxfimm/iqab004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7928677PMC
February 2021

Omega-3 polyunsaturated fatty acids protect against inflammation through production of LOX and CYP450 lipid mediators: relevance for major depression and for human hippocampal neurogenesis.

Mol Psychiatry 2021 Jun 16. Epub 2021 Jun 16.

Stress, Psychiatry and Immunology Laboratory, Institute of Psychiatry, Psychology and Neuroscience, Department of Psychological Medicine, King's College London, London, UK.

Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) can exert antidepressant, anti-inflammatory and neuroprotective properties, but the exact molecular mechanism underlying their effects is still not fully understood. We conducted both in vitro and clinical investigations to test which EPA or DHA metabolites are involved in these anti-inflammatory, neuroprotective and antidepressant effects. In vitro, we used the human hippocampal progenitor cell line HPC0A07/03C, and pre-treated cells with either EPA or DHA, followed by interleukin 1beta (IL1β), IL6 and interferon-alpha (IFN-α). Both EPA and DHA prevented the reduction in neurogenesis and the increase in apoptosis induced by these cytokines; moreover, these effects were mediated by the lipoxygenase (LOX) and cytochrome P450 (CYP450) EPA/DHA metabolites, 5-hydroxyeicosapentaenoic acid (HEPE), 4-hydroxydocosahexaenoic acid (HDHA), 18-HEPE, 20-HDHA, 17(18)-epoxyeicosatetraenoic acid (EpETE) and 19(20)-epoxydocosapentaenoic acid (EpDPA), detected here for the first time in human hippocampal neurones using mass spectrometry lipidomics of the supernatant. In fact, like EPA/DHA, co-treatment with these metabolites prevented cytokines-induced reduction in neurogenesis and apoptosis. Moreover, co-treatment with 17(18)-EpETE and 19(20)-EpDPA and the soluble epoxide hydroxylase (sEH) inhibitor, TPPU (which prevents their conversion into dihydroxyeicosatetraenoic acid (DiHETE)/ dihydroxydocosapentaenoic acid (DiHDPA) metabolites) further enhanced their neurogenic and anti-apoptotic effects. Interestingly, these findings were replicated in a sample of n = 22 patients with a DSM-IV Major Depressive Disorder, randomly assigned to treatment with either EPA (3.0 g/day) or DHA (1.4 g/day) for 12 weeks, with exactly the same LOX and CYP450 lipid metabolites increased in the plasma of these patients following treatment with their precursor, EPA or DHA, and some evidence that higher levels of these metabolites were correlated with less severe depressive symptoms. Overall, our study provides the first evidence for the relevance of LOX- and CYP450-derived EPA/DHA bioactive lipid metabolites as neuroprotective molecular targets for human hippocampal neurogenesis and depression, and highlights the importance of sEH inhibitors as potential therapeutic strategy for patients suffering from depressive symptoms.
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http://dx.doi.org/10.1038/s41380-021-01160-8DOI Listing
June 2021

Maternal depression during pregnancy alters infant subcortical and midbrain volumes.

J Affect Disord 2021 08 14;291:163-170. Epub 2021 May 14.

Sackler Institute for Translational Neurodevelopment, Department of Forensic and Neurodevelopmental Sciences, Institute of Psychiatry, Psychology & Neuroscience, King's College London, UK; NIHR Biomedical Research Centre for Mental Health at the South London and Maudsley NHS Foundation Trust and King's College London, UK.

Background: Maternal depression in pregnancy increases the risk for adverse neurodevelopmental outcomes in the offspring. The reason for this is unknown, however, one plausible mechanism may include the impact of maternal antenatal depression on infant brain. Nevertheless, relatively few studies have examined the brain anatomy of infants born to clinically diagnosed mothers.

Methods: A legacy magnetic resonance imaging (MRI) dataset was used to compare regional brain volumes in 3-to-6-month-old infants born to women with a clinically confirmed diagnosis of major depressive disorder (MDD) during pregnancy (n = 31) and a reference sample of infants born to women without a current or past psychiatric diagnosis (n = 33). A method designed for analysis of low-resolution scans enabled examination of subcortical and midbrain regions previously found to be sensitive to the parent-child environment.

Results: Compared with infants of non-depressed mothers, infants exposed to maternal antenatal depression had significantly larger subcortical grey matter volumes and smaller midbrain volumes. There was no association between gestational medication exposure and the infant regional brain volumes examined in our sample.

Limitations: Our scanning approach did not allow for an examination of fine-grained structural differences, and without repeated measures of brain volume, it is unknown whether the direction of reported associations are dependent on developmental stage.

Conclusions: Maternal antenatal depression is associated with an alteration in infant brain anatomy in early postnatal life; and that this is not accounted for by medication exposure. However, our study cannot address whether anatomical differences impact on future outcomes of the offspring.
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http://dx.doi.org/10.1016/j.jad.2021.05.008DOI Listing
August 2021

Mother-infant interaction in women with depression in pregnancy and in women with a history of depression: the Psychiatry Research and Motherhood - Depression (PRAM-D) study.

BJPsych Open 2021 May 25;7(3):e100. Epub 2021 May 25.

Department of Psychological Medicine, Institute of Psychiatry, Psychology and Neuroscience, King's College London, UK.

Background: Little is known about the effects of depression before birth on the quality of the mother-infant interaction.

Aims: To understand whether depression, either in pregnancy or in lifetime before pregnancy, disrupts postnatal mother-infant interactions.

Method: We recruited 131 pregnant women (51 healthy, 52 with major depressive disorder (MDD) in pregnancy, 28 with a history of MDD but healthy pregnancy), at 25 weeks' gestation. MDD was confirmed with the Structured Clinical Interview for DSM-IV Disorders. Neonatal behaviour was assessed at 6 days with the Neonatal Behavioural Assessment Scale, and mother-infant interaction was assessed at 8 weeks and 12 months with the Crittenden CARE-Index.

Results: At 8 weeks and 12 months, dyads in the depression and history-only groups displayed a reduced quality of interaction compared with healthy dyads. Specifically, at 8 weeks, 62% in the depression group and 56% in the history-only group scored in the lowest category of dyadic synchrony (suggesting therapeutic interventions are needed), compared with 37% in the healthy group (P = 0.041); 48% and 32%, respectively, scored the same at 12 months, compared with 14% in the healthy group (P = 0.003). At 6 days, neonates in the depression and history-only groups exhibited decreased social-interactive behaviour, which, together with maternal socioeconomic difficulties, was also predictive of interaction quality, whereas postnatal depression was not.

Conclusions: Both antenatal depression and a lifetime history of depression are associated with a decreased quality of mother-infant interaction, irrespective of postnatal depression. Clinicians should be aware of this, as pregnancy provides an opportunity for identification and intervention to support the developing relationship.
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http://dx.doi.org/10.1192/bjo.2021.52DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8167851PMC
May 2021

Elevated C-Reactive Protein in Patients With Depression, Independent of Genetic, Health, and Psychosocial Factors: Results From the UK Biobank.

Am J Psychiatry 2021 06 14;178(6):522-529. Epub 2021 May 14.

Department of Psychological Medicine, Institute of Psychiatry, Psychology and Neuroscience (Pitharouli, Hotopf, Pariante), and Social, Genetic and Developmental Psychiatry Centre (Pitharouli, Hagenaars, Glanville, Coleman, Lewis), King's College London, London; National Institute for Health Research, Maudsley Biomedical Research Centre, South London and Maudsley National Health Service Foundation Trust, London (Hotopf, Lewis, Pariante).

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.
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http://dx.doi.org/10.1176/appi.ajp.2020.20060947DOI Listing
June 2021

Altered dynamics of the prefrontal networks are associated with the risk for postpartum psychosis: a functional magnetic resonance imaging study.

Transl Psychiatry 2021 05 12;11(1):238. Epub 2021 May 12.

Department of Psychological Medicine, Institute of Psychiatry, Psychology & Neuroscience, King's College London, De Crespigny Park, London, UK.

Postpartum psychosis (PP) is a severe mental disorder that affects women in the first few weeks after delivery. To date there are no biomarkers that distinguish which women at risk (AR) develop a significant psychiatric relapse postpartum. While altered brain connectivity may contribute to the risk for psychoses unrelated to the puerperium, this remains unexplored in PP. We followed up 32 AR and 27 healthy (HC) women from pregnancy to 8-week postpartum. At this point, we classified women as AR-unwell (n = 15) if they had developed a psychiatric relapse meeting DSM-IV diagnostic criteria, or impacting on daily functioning and requiring treatment, or AR-well (n = 17) if they remained asymptomatic. Women also underwent an fMRI scan at rest and during an emotional-processing task, to study within- and between-networks functional connectivity. Women AR, and specifically those in the AR-well group, showed increased resting connectivity within an executive network compared to HC. During the execution of the emotional task, women AR also showed decreased connectivity in the executive network, and altered emotional load-dependent connectivity between executive, salience, and default-mode networks. AR-unwell women particularly showed increased salience network-dependent modulation of the default-mode and executive network relative to AR-well, who showed greater executive network-dependent modulation of the salience network. Our finding that the executive network and its interplay with other brain networks implicated in goal-directed behavior are intrinsically altered suggest that they could be considered neural phenotypes for postpartum psychosis and help advance our understanding of the pathophysiology of this disorder.
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http://dx.doi.org/10.1038/s41398-021-01351-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8113224PMC
May 2021

Risk factors for postpartum relapse in women at risk of postpartum psychosis: The role of psychosocial stress and the biological stress system.

Psychoneuroendocrinology 2021 06 3;128:105218. Epub 2021 Apr 3.

Department of Psychological Medicine, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London SE5 8AF, UK. Electronic address:

Background: Postpartum psychosis is the most severe psychiatric disorder associated with childbirth, and the risk is particularly high for women with a history of bipolar disorder, schizoaffective disorder or those who have suffered a previous episode of postpartum psychosis. Whilst there is a lot of evidence linking stress to psychosis unrelated to childbirth, the role of stress in the onset of postpartum psychosis has not been fully investigated.

Methods: A prospective longitudinal study of 112 pregnant women, 51 at risk of postpartum psychosis because of a DSM-IV diagnosis of bipolar disorder (n = 41), schizoaffective disorder (n = 6) or a previous postpartum psychosis (n = 4) and 61 healthy women with no past or current DSM-IV diagnosis and no family history of postpartum psychosis. Women were followed up from the third trimester of pregnancy to 4 weeks' post partum. Women at risk who had a psychiatric relapse in the first 4 weeks' post partum (AR-unwell) (n = 22), were compared with those at risk who remained well (AR-well) (n = 29) on measures of psychosocial stress (severe childhood maltreatment and stressful life events) and biological stress (cortisol and inflammatory biomarkers).

Results: Logistic regression analyses revealed that severe childhood maltreatment (OR = 4.9, 95% CI 0.5-49.2) and higher daily cortisol in the third trimester of pregnancy (OR=3.7, 95% CI 1.2-11.6) predicted psychiatric relapse in the first 4 weeks' post partum in women at risk of postpartum psychosis after adjusting for clinical and sociodemographic covariates.

Conclusion: The current study provides evidence for the role of psychosocial stress and the biological stress system in the risk of postpartum relapse in women at risk of postpartum psychosis.
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http://dx.doi.org/10.1016/j.psyneuen.2021.105218DOI Listing
June 2021

Structural Covariance of Cortical Gyrification at Illness Onset in Treatment Resistance: A Longitudinal Study of First-Episode Psychoses.

Schizophr Bull 2021 Oct;47(6):1729-1739

Department of Psychosis Studies, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK.

Treatment resistance (TR) in patients with first-episode psychosis (FEP) is a major cause of disability and functional impairment, yet mechanisms underlying this severe disorder are poorly understood. As one view is that TR has neurodevelopmental roots, we investigated whether its emergence relates to disruptions in synchronized cortical maturation quantified using gyrification-based connectomes. Seventy patients with FEP evaluated at their first presentation to psychiatric services were followed up using clinical records for 4 years; of these, 17 (24.3%) met the definition of TR and 53 (75.7%) remained non-TR at 4 years. Structural MRI images were obtained within 5 weeks from first exposure to antipsychotics. Local gyrification indices were computed for 148 contiguous cortical regions using FreeSurfer; each subject's contribution to group-based structural covariance was quantified using a jack-knife procedure, providing a single deviation matrix for each subject. The latter was used to derive topological properties that were compared between TR and non-TR patients using a Functional Data Analysis approach. Compared to the non-TR patients, TR patients showed a significant reduction in small-worldness (Hedges's g = 2.09, P < .001) and a reduced clustering coefficient (Hedges's g = 1.07, P < .001) with increased length (Hedges's g = -2.17, P < .001), indicating a disruption in the organizing principles of cortical folding. The positive symptom burden was higher in patients with more pronounced small-worldness (r = .41, P = .001) across the entire sample. The trajectory of synchronized cortical development inferred from baseline MRI-based structural covariance highlights the possibility of identifying patients at high-risk of TR prospectively, based on individualized gyrification-based connectomes.
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http://dx.doi.org/10.1093/schbul/sbab035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8530394PMC
October 2021

The influence of comorbid depression and overweight status on peripheral inflammation and cortisol levels.

Psychol Med 2021 Mar 18:1-8. Epub 2021 Mar 18.

Department of Psychological Medicine, King's College London, Institute of Psychiatry, Psychology and Neuroscience, London, UK.

Background: Depression and overweight are each associated with abnormal immune system activation. We sought to disentangle the extent to which depressive symptoms and overweight status contributed to increased inflammation and abnormal cortisol levels.

Methods: Participants were recruited through the Wellcome Trust NIMA Consortium. The sample of 216 participants consisted of 69 overweight patients with depression; 35 overweight controls; 55 normal-weight patients with depression and 57 normal-weight controls. Peripheral inflammation was measured as high-sensitivity C-Reactive Protein (hsCRP) in serum. Salivary cortisol was collected at multiple points throughout the day to measure cortisol awakening response and diurnal cortisol levels.

Results: Overweight patients with depression had significantly higher hsCRP compared with overweight controls (p = 0.042), normal-weight depressed patients (p < 0.001) and normal-weight controls (p < 0.001), after controlling for age and gender. Multivariable logistic regression showed that comorbid depression and overweight significantly increased the risk of clinically elevated hsCRP levels ⩾3 mg/L (OR 2.44, 1.28-3.94). In a separate multivariable logistic regression model, overweight status contributed most to the risk of having hsCRP levels ⩾3 mg/L (OR 1.52, 0.7-2.41), while depression also contributed a significant risk (OR 1.09, 0.27-2). There were no significant differences between groups in cortisol awakening response and diurnal cortisol levels.

Conclusion: Comorbid depression and overweight status are associated with increased hsCRP, and the coexistence of these conditions amplified the risk of clinically elevated hsCRP levels. Overweight status contributed most to the risk of clinically elevated hsCRP levels, but depression also contributed to a significant risk. We observed no differences in cortisol levels between groups.
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http://dx.doi.org/10.1017/S0033291721000088DOI Listing
March 2021

The Role of Peripheral Inflammation in Clinical Outcome and Brain Imaging Abnormalities in Psychosis: A Systematic Review.

Front Psychiatry 2021 19;12:612471. Epub 2021 Feb 19.

Department of Psychological Medicine, King's College London, Institute of Psychiatry, Psychology and Neuroscience, London, United Kingdom.

Promising research investigating the association between inflammatory biomarkers and response to antipsychotic and/or adjunctive therapy, observed by improvement in psychiatric assessment, is emerging. Increased inflammation has been suggested to contribute to higher severity of symptoms/treatment resistance through the effects that this has on brain structure and function. The present systematic review aims to clarify the potential role of peripheral inflammatory markers as predictors of clinical outcomes and their association with neuroimaging markers in patients with psychosis. Systematic searches of the literature using the databases PsychInfo, OVID Medline, and Embase were conducted to collate studies investigating the association of inflammatory biomarkers with clinical outcome in patients with psychotic disorders and studies examining the relationships between inflammatory biomarkers and neuroimaging data. Seventeen studies on predictors of clinical outcome and 14 on associations between neuroimaging data and inflammatory biomarkers in psychosis were identified, and risk of bias was assessed using the Newcastle-Ottawa Scale (NOS). The main inflammatory markers associated with clinical outcome in psychosis were interleukin (IL)-6, IL-10, and C-reactive protein (CRP). High levels of CRP and IL-6 were associated with worse clinical outcome and deterioration of symptoms over time; in contrast, increased levels of IL-10 were associated with greater symptoms improvement. Smaller hippocampal volume and reduced cortical thickness were the main neuroimaging markers associated with increased peripheral inflammation. The heterogeneity across the studies (i.e., treatments strategies, duration) suggests that potential prediction power of inflammatory biomarkers could partially depend on the methodologies, supported by the overall NOS ratings of the studies. Future studies may need to consider whether a combination of these inflammatory and neuroimaging markers could further improve our ability of predicting clinical outcome in patients with psychosis.
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http://dx.doi.org/10.3389/fpsyt.2021.612471DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7933584PMC
February 2021

Corrigendum: The Long-Term Effects of Early Life Stress on the Modulation of miR-19 Levels.

Front Psychiatry 2020 15;11:643932. Epub 2021 Feb 15.

Biological Psychiatry Unit, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy.

[This corrects the article DOI: 10.3389/fpsyt.2020.00389.].
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http://dx.doi.org/10.3389/fpsyt.2020.643932DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7928271PMC
February 2021

Severe mental illness and European COVID-19 vaccination strategies.

Lancet Psychiatry 2021 05 17;8(5):356-359. Epub 2021 Feb 17.

IMRB Translational Neuropsychiatry Lab, Université Paris Est Creteil, Creteil, France; Department of Psychiatry and Addictology, Hôpitaux Universitaires Henri Mondor, Créteil, France; Fondation FondaMental, Creteil, France.

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http://dx.doi.org/10.1016/S2215-0366(21)00046-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7906735PMC
May 2021

The three frontlines against COVID-19: Brain, Behavior, and Immunity.

Brain Behav Immun 2021 03 4;93:409-414. Epub 2021 Feb 4.

Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.

The pandemic outbreak of coronavirus disease 2019 (COVID-19) is raising global anxiety and fear of both real and perceived health threat from the virus. Overwhelming evidence shows infected patients experiencing neuropsychiatric complications, suggesting that the "psychoneuroimmunity" model might be beneficial in understanding the impact of the virus. Therefore, this Special Issue on "Immunopsychiatry of COVID-19 Pandemic" was launched immediately after the pandemic was declared, with the first paper accepted on the March 25th, 2020. A total of ninety-three papers were accepted, the last one was on the July 10th, 2020 when the initial acute phase started declining. The papers of this Special Issue have illuminated the social impact, psychopathology, neurological manifestation, immunity responses, and potential treatments and prevention on COVID-19. For example, anxiety disorders, mood disorders, and suicidal ideation are most common psychiatric manifestations. COVID-19 infection can have central and/or peripheral nervous system symptoms, including headache, sleep disorders, encephalopathy, and loss of taste and smell. A "three-steps" Neuro-COVID infection model (neuro-invasion, clearance and immune response) was established. The current therapeutic interventions for COVID-19 include supportive intervention, immunomodulatory agents, antiviral therapy, and plasma transfusion. Psychological support should be implemented, improving the psychological wellbeing, as well as to enhance psychoneuroimmunity against COVID-19.
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http://dx.doi.org/10.1016/j.bbi.2021.01.030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7857976PMC
March 2021

Chronic stress induces significant gene expression changes in the prefrontal cortex alongside alterations in adult hippocampal neurogenesis.

Brain Commun 2020 26;2(2):fcaa153. Epub 2020 Sep 26.

Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London SE5 9NU, UK.

Adult hippocampal neurogenesis is involved in stress-related disorders such as depression, posttraumatic stress disorders, as well as in the mechanism of antidepressant effects. However, the molecular mechanisms involved in these associations remain to be fully explored. In this study, unpredictable chronic mild stress in mice resulted in a deficit in neuronal dendritic tree development and neuroblast migration in the hippocampal neurogenic niche. To investigate molecular pathways underlying neurogenesis alteration, genome-wide gene expression changes were assessed in the prefrontal cortex, hippocampus and the hypothalamus alongside neurogenesis changes. Cluster analysis showed that the transcriptomic signature of chronic stress is much more prominent in the prefrontal cortex compared to the hippocampus and the hypothalamus. Pathway analyses suggested huntingtin, leptin, myelin regulatory factor, methyl-CpG binding protein and brain-derived neurotrophic factor as the top predicted upstream regulators of transcriptomic changes in the prefrontal cortex. Involvement of the satiety regulating pathways (leptin) was corroborated by behavioural data showing increased food reward motivation in stressed mice. Behavioural and gene expression data also suggested circadian rhythm disruption and activation of circadian clock genes such as Period 2. Interestingly, most of these pathways have been previously shown to be involved in the regulation of adult hippocampal neurogenesis. It is possible that activation of these pathways in the prefrontal cortex by chronic stress indirectly affects neuronal differentiation and migration in the hippocampal neurogenic niche via reciprocal connections between the two brain areas.
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http://dx.doi.org/10.1093/braincomms/fcaa153DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7850288PMC
September 2020

A Modest Increase in C-PK11195-Positron Emission Tomography TSPO Binding in Depression Is Not Associated With Serum C-Reactive Protein or Body Mass Index.

Biol Psychiatry Cogn Neurosci Neuroimaging 2021 07 28;6(7):716-724. Epub 2021 Jan 28.

Department of Neuroimaging, Institute of Psychiatry, Psychology and Neuroscience, King's College London, United Kingdom.

Background: Immune mechanisms have been implicated in the pathogenesis of depression. Translocator protein (TSPO)-targeted positron emission tomography (PET) has been used to assess neuroinflammation in major depressive disorder. We aimed to 1) test the hypothesis of significant case-control differences in TSPO binding in the anterior cingulate cortex, prefrontal cortex, and insula regions; and 2) explore the relationship between cerebral TSPO binding and peripheral blood C-reactive protein (CRP) concentration.

Methods: A total of 51 depressed subjects with Hamilton Depression Rating Scale score >13 (median 17; interquartile range, 16-22) and 25 healthy control subjects underwent dynamic brain C-PK11195 PET and peripheral blood immune marker characterization. Depressed subjects were divided into high CRP (>3 mg/L; n = 20) and low CRP (<3 mg/L; n = 31).

Results: Across the three regions, TSPO binding was significantly increased in depressed versus control subjects (η = .09; F = 6.97, p = .01), which was not influenced by body mass index. The case-control difference was greatest in the anterior cingulate cortex (d = 0.49; t = 2.00, p = .03) and not significant in the prefrontal cortex or insula (d = 0.27 and d = 0.36, respectively). Following CRP stratification, significantly higher TSPO binding was observed in low-CRP depression compared with controls (d = 0.53; t = 1.96, p = .03). These effect sizes are comparable to prior major depressive disorder case-control TSPO PET data. No significant correlations were observed between TSPO and CRP measures.

Conclusions: Consistent with previous findings, there is a modest increase in TSPO binding in depressed patients compared with healthy control subjects. The lack of a significant correlation between brain TSPO binding and blood CRP concentration or body mass index poses questions about the interactions between central and peripheral immune responses in the pathogenesis of depression.
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http://dx.doi.org/10.1016/j.bpsc.2020.12.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8264953PMC
July 2021

Augmentation therapy with minocycline in treatment-resistant depression patients with low-grade peripheral inflammation: results from a double-blind randomised clinical trial.

Neuropsychopharmacology 2021 04 28;46(5):939-948. Epub 2021 Jan 28.

King's College London, Institute of Psychiatry Psychology and Neuroscience, Department of Psychological Medicine, London, UK.

This study aimed to investigate the role of baseline levels of peripheral inflammation when testing the efficacy of antidepressant augmentation with minocycline in patients with treatment-resistant depression. We conducted a 4-week, placebo-controlled, randomised clinical trial of minocycline (200 mg/day) added to antidepressant treatment in 39 patients selected for elevated levels of serum C-reactive protein (CRP ≥ 1 mg/L), n = 18 randomised to minocycline (M) and n = 21 to placebo (P). The main outcome was the change in Hamilton Depression Rating Scale (HAM-D-17) score from baseline to week 4, expressed both as mean and as full or partial response, in the overall sample and after further stratification for baseline CRP≥3 mg/L. Secondary outcomes included changes in other clinical and inflammatory measures. Changes in HAM-D-17 scores and the proportion of partial responders did not differ between study arms. After stratification for CRP levels <3 mg/L (CRP) or ≥3 mg/L (CRP), CRP/M patients showed the largest changes in HAM-D-17 scores (mean ± SD = 12.00 ± 6.45) compared with CRP/M (2.42 ± 3.20, p < 0.001), CRP/P (3.50 ± 4.34, p = 0.003) and CRP/P (2.11 ± 3.26, p = 0.006) patients, and the largest proportion (83.3%, p = 0.04) of partial treatment response at week 4. The threshold point for baseline CRP to distinguish responders from non-responders to minocycline was 2.8 mg/L. Responders to minocycline had higher baseline IL-6 concentrations than non-responders (p = 0.03); IFNγ was significantly reduced after treatment with minocycline compared with placebo (p = 0.03). Our data show some evidence of efficacy of add-on treatment with minocycline in MDD patients but only in those with low-grade inflammation defined as CRP ≥3 mg/L.
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http://dx.doi.org/10.1038/s41386-020-00948-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8096832PMC
April 2021

Associations of Dietary Intake on Biological Markers of Inflammation in Children and Adolescents: A Systematic Review.

Nutrients 2021 Jan 25;13(2). Epub 2021 Jan 25.

Stress, Psychiatry and Immunology Laboratory, Department of Psychological Medicine, Institute of Psychiatry, Psychology & Neuroscience, King's College, London SE5 9RT, UK.

Background: In children and adolescents, chronic low-grade inflammation has been implicated in the pathogenesis of co- and multi-morbid conditions to mental health disorders. Diet quality is a potential mechanism of action that can exacerbate or ameliorate low-grade inflammation; however, the exact way dietary intake can regulate the immune response in children and adolescents is still to be fully understood.

Methods: Studies that measured dietary intake (patterns of diet, indices, food groups, nutrients) and any inflammatory biomarkers in children and adolescents aged 2 to19 years and published until November 2020 were included in this systematic review, and were selected in line with PRISMA guidelines through the following databases: Academic Search Complete, CINAHL, Global Health, Medline COMPLETE and Web of Science-Core Collection. A total of 53 articles were identified.

Results: Results show that adequate adherence to healthful dietary patterns such as the Mediterranean diet, or food groups such as vegetables and fruit, or macro/micro nutrients such as fibre or vitamin C and E, are associated with decreased levels of pro-inflammatory biomarkers, mainly c-reactive protein (CRP), interleukin-6 (IL-6) and tumour necrosis factor-alpha (TNF-α), whereas adherence to a Western dietary pattern, as well as intake of food groups such as added sugars, macro-nutrients such as saturated fatty acids or ultra-processed foods, is associated with higher levels of the same pro-inflammatory biomarkers.

Conclusions: This is the first systematic review examining dietary intake and biological markers of inflammation in both children and adolescents. A good quality diet, high in vegetable and fruit intake, wholegrains, fibre and healthy fats ameliorates low-grade inflammation, and therefore represents a promising therapeutic approach, as well as an important element for disease prevention in both children and adolescents.
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http://dx.doi.org/10.3390/nu13020356DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7911843PMC
January 2021

Alterations in 'inflammatory' pathways in the rat prefrontal cortex as early biological predictors of the long-term negative consequences of exposure to stress early in life.

Psychoneuroendocrinology 2021 02 6;124:104794. Epub 2020 Jul 6.

Biological Psychiatry Unit, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy; Department of Pharmacological and Biomolecular Sciences, University of Milan, Italy. Electronic address:

Early life stress, especially when experienced during the first period of life, affects the brain developmental trajectories leading to an enhanced vulnerability for stress-related psychiatric disorders later in life. Although both clinical and preclinical studies clearly support this association, the biological pathways deregulated by such exposure, and the effects in shaping the neurodevelopmental trajectories, have so far been poorly investigated. By using the prenatal stress (PNS) model, a well-established rat model of early life stress, we performed transcriptomic analyses in the prefrontal cortex of rats exposed or not to PNS and sacrificed at different postnatal days (PNDs 21, 40, 62). We first investigated the long-lasting mechanisms and pathways affected in the PFC. We have decided to focus on the prefrontal cortex because we have previously shown that this brain region is highly sensitive to PNS exposure. We found that adult animals exposed to PNS show alterations in 389 genes, mainly involved in stress and inflammatory signalling. We then wanted to establish whether PNS exposure could also affect the neurodevelopmental trajectories in order to identify the most critical temporal window. We found that PNS rats show the most significant changes during adolescence (between PND 40 versus PND 21), with alterations of several pathways related to stress, inflammation and metabolism, which were maintained until adulthood.
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http://dx.doi.org/10.1016/j.psyneuen.2020.104794DOI Listing
February 2021
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