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The rising prevalence and legalisation of cannabis worldwide have underscored the need for a comprehensive understanding of its biological impact, particularly on mental health. Epigenetic mechanisms, specifically DNA methylation, have gained increasing recognition as vital factors in the interplay between risk factors and mental health. This study aimed to explore the effects of current cannabis use and high-potency cannabis on DNA methylation in two independent cohorts of individuals experiencing first-episode psychosis (FEP) compared to control subjects. The combined sample consisted of 682 participants (188 current cannabis users and 494 never users). DNA methylation profiles were generated on blood-derived DNA samples using the Illumina DNA methylation array platform. A meta-analysis across cohorts identified one CpG site (cg11669285) in the CAVIN1gene that showed differential methylation with current cannabis use, surpassing the array-wide significance threshold, and independent of the tobacco-related epigenetic signature. Furthermore, a CpG site localised in the MCUgene (cg11669285) achieved array-wide significance in an analysis of the effect of high-potency (THC = > 10%) current cannabis use. Pathway and regional analyses identified cannabis-related epigenetic variation proximal to genes linked to immune and mitochondrial function, both of which are known to be influenced by cannabinoids. Interestingly, a model including an interaction term between cannabis use and FEP status identified two sites that were significantly associated with current cannabis use with a nominally significant interaction suggesting that FEP status might moderate how cannabis use affects DNA methylation. Overall, these findings contribute to our understanding of the epigenetic impact of current cannabis use and highlight potential molecular pathways affected by cannabis exposure.

Globally, too many people die prematurely from suicide and the physical comorbidities associated with mental illness and mental distress. The purpose of this Review is to mobilise the translation of evidence into prioritised actions that reduce this inequity. The mental health research charity, MQ Mental Health Research, convened an international panel that used roadmapping methods and review evidence to identify key factors, mechanisms, and solutions for premature mortality across the social–ecological system. We identified 12 key overarching risk factors and mechanisms, with more commonalities than differences across the suicide and physical comorbidities domains. We also identified 18 actionable solutions across three organising principles: the integration of mental and physical health care; the prioritisation of prevention while strengthening treatment; and the optimisation of intervention synergies across social–ecological levels and the intervention cycle. These solutions included accessible, integrated high-quality primary care; early life, workplace, and community-based interventions co-designed by the people they should serve; decriminalisation of suicide and restriction of access to lethal means; stigma reduction; reduction of income, gender, and racial inequality; and increased investment. The time to act is now, to rebuild health-care systems, leverage changes in funding landscapes, and address the effects of stigma, discrimination, marginalisation, gender violence, and victimisation.

There have been significant challenges in understanding functional brain connectivity associated with adolescent depression, including the need for a more comprehensive approach to defining risk, the lack of representation of participants from low- and middle-income countries, and the need for network-based approaches to model connectivity. The current study aimed to address these challenges by examining resting-state functional connectivity of frontolimbic circuitry associated with the risk and presence of depression in adolescents in Brazil.

Lo stress rappresenta la risposta di adattamento dell’organismo a una minaccia all’equilibrio (omeostasi) dell’organismo da parte di eventi o stressordi natura intrinseca o estrinseca, reali o percepiti. Gli stressorattivano un variegato e intricato repertorio di risposte fisiologiche biologiche e comportamentali (allostasi) volte a ristabilire l’equilibrio ottimale dell’organismo (eustasi). La risposta adattiva agli stressordipende da una complessa rete psico-neuro-endocrino-immuno-metabolica, cellulare e molecolare altamente interconnessa, chiamata proprio sistema o asse dello stress. I componenti chiave sono rappresentati dall’asse ipotalamo-ipofisi-surrene (HPA) e dal sistema nervoso autonomo (SNA), che interagiscono con altri centri vitali del sistema nervoso centrale (SNC) e con organi periferici e sistemi, dalla cui attivazione complessiva si genera una risposta rapida, efficace, multisistemica e autolimitantesi, che permette all’organismo una reazione corporea e neuropsichica ottimale. Le catecolamine e il cortisolo rappresentano gli attori principali che esplicano e attivano le reazioni psichiche e comportamentali dell’individuo nella reazione di stress, la cosiddetta reazione fight or flight. L’azione delle catecolamine è breve, quella del cortisolo più duratura e mediata dall’attivazione dei recettori del cortisolo (GR e MR, recettori dei glucocorticoidi e mineralcorticoidi rispettivamente) espressi ubiquitariamente. Attraverso azioni non genomiche e genomiche i glucocorticoidi modulano una serie di processi metabolici, con caratteristiche sesso specifiche. Una delle conseguenze della reazione dello stress, in condizioni in cui quest’ultimo sia persistente o non adeguatamente regolato, è lo sviluppo di uno stato infiammatorio cronico. Il cortisolo ha un ruolo rilevante nell’equilibrio citochinico pro/antinfiammatorio. In condizioni di stress cronico questo equilibrio viene meno e si crea uno scenario caratterizzato da risposte infiammatorie eccessive. È oggi definito il ruolo dello stato infiammatorio cronico nella fisiopatologia della sindrome metabolica, dell’obesità e del diabete, così come della depressione. In questa rassegna percorreremo, sulla base delle evidenze della letteratura, i meccanismi psico-neuro-endocrino-metabolici sottesi alla regolazione dello stress e alle conseguenze metaboliche e psichiche potenzialmente generabili e correlate allo stress cronico o all’alterata regolazione dello stesso.

Schizophrenia has a heritability of 60–80%1, much of which is attributable to common risk alleles. Here, in a two-stage genome-wide association study of up to 76,755 individuals with schizophrenia and 243,649 control individuals, we report common variant associations at 287 distinct genomic loci. Associations were concentrated in genes that are expressed in excitatory and inhibitory neurons of the central nervous system, but not in other tissues or cell types. Using fine-mapping and functional genomic data, we identify 120 genes (106 protein-coding) that are likely to underpin associations at some of these loci, including 16 genes with credible causal non-synonymous or untranslated region variation. We also implicate fundamental processes related to neuronal function, including synaptic organization, differentiation and transmission. Fine-mapped candidates were enriched for genes associated with rare disruptive coding variants in people with schizophrenia, including the glutamate receptor subunit GRIN2Aand transcription factor SP4, and were also enriched for genes implicated by such variants in neurodevelopmental disorders. We identify biological processes relevant to schizophrenia pathophysiology; show convergence of common and rare variant associations in schizophrenia and neurodevelopmental disorders; and provide a resource of prioritized genes and variants to advance mechanistic studies.

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.

To present the protocol and methods for the prospective longitudinal assessments—including clinical and digital phenotyping approaches—of the Identifying Depression Early in Adolescence Risk Stratified Cohort (IDEA-RiSCo) study, which comprises Brazilian adolescents stratified at baseline by risk of developing depression or presence of depression.

To date, gene-environment (GxE) interaction studies in depression have been limited to hypothesis-based candidate genes, since genome-wide (GWAS)-based GxE interaction studies would require enormous datasets with genetics, environmental, and clinical variables. We used a novel, cross-species and cross-tissues “omics” approach to identify genes predicting depression in response to stress in GxE interactions. We integrated the transcriptome and miRNome profiles from the hippocampus of adult rats exposed to prenatal stress (PNS) with transcriptome data obtained from blood mRNA of adult humans exposed to early life trauma, using a stringent statistical analyses pathway. Network analysis of the integrated gene lists identified the Forkhead box protein O1 (FoxO1), Alpha-2-Macroglobulin (A2M), and Transforming Growth Factor Beta 1 (TGF-β1) as candidates to be tested for GxE interactions, in two GWAS samples of adults either with a range of childhood traumatic experiences (Grady Study Project, Atlanta, USA) or with separation from parents in childhood only (Helsinki Birth Cohort Study, Finland). After correction for multiple testing, a meta-analysis across both samples confirmed six FoxO1SNPs showing significant GxE interactions with early life emotional stress in predicting depressive symptoms. Moreover, in vitro experiments in a human hippocampal progenitor cell line confirmed a functional role of FoxO1in stress responsivity. In secondary analyses, A2Mand TGF-β1showed significant GxE interactions with emotional, physical, and sexual abuse in the Grady Study. We therefore provide a successful ‘hypothesis-free’ approach for the identification and prioritization of candidate genes for GxE interaction studies that can be investigated in GWAS datasets.

The role of omega-3 polyunsaturated fatty acids (omega-3 or n-3 PUFAs) in the pathogenesis and treatment of children and adolescents with attention deficit hyperactivity disorder (ADHD) is unclear. A systematic review followed by meta-analysis was conducted on: (1) randomized controlled trials (RCTs) assessing the effects of n-3 PUFAs on clinical symptoms and cognition in children and adolescent with ADHD; and (2) case–control studies assessing the levels of n-3 PUFAs in blood and buccal tissues of children and adolescents with ADHD. In seven RCTs, totalling n=534 randomized youth with ADHD, n-3 PUFAs supplementation improves ADHD clinical symptom scores (g=0.38, p<0.0001); and in three RCTs, totalling n=214 randomized youth with ADHD, n-3 PUFAs supplementation improves cognitive measures associated with attention (g=1.09, p=0.001). Moreover, children and adolescents with ADHD have lower levels of DHA (seven studies, n=412, g=−0.76, p=0.0002), EPA (seven studies, n=468, g=−0.38, p=0.0008), and total n-3 PUFAs (six studies, n=396, g=−0.58, p=0.0001). In summary, there is evidence that n-3 PUFAs supplementation monotherapy improves clinical symptoms and cognitive performances in children and adolescents with ADHD, and that these youth have a deficiency in n-3 PUFAs levels. Our findings provide further support to the rationale for using n-3 PUFAs as a treatment option for ADHD.

The role of immune activation in psychiatric disorders has attracted considerable attention over the past two decades, contributing to the rise of a new era for psychiatry. Microglia, the macrophages of the brain, are progressively becoming the main focus of the research in this field. In this Review, we assess the literature on microglia activation across different psychiatric disorders, including post-mortem and in-vivo studies in humans and experimental studies in animals. Although microglia activation has been noted in all types of psychiatric disorder, no association was seen with specific diagnostic categories. Furthermore, the findings from these studies highlight that not all psychiatric patients have microglial activation. Therefore, the cause of the neuroinflammation in these cohorts and its implications are unclear. We discuss psychosocial stress as one of the main factors determining microglial activation in patients with psychiatric disorders, and explore the relevance of these findings for future treatment strategies.

This paper describes the effects of immune genes genetic variants and mRNA expression on depression’s risk, severity, and response to antidepressant treatment, through a systematic review on all papers published between 2000 and 2016. Our results, based largely on case–control studies, suggest that common genetic variants and gene-expression pathways are involved in both immune activation and depression. The most replicated and relevant genetic variants include polymorphisms in the genes for interleukin (IL)-1β, IL-6, IL-10, monocyte chemoattractant protein-1, tumor necrosis factor-alpha, C-reactive protein, and phospholipase A2. Moreover, increased blood cytokines mRNA expression (especially of IL-1β) identifies patients that are less likely to respond to conventional antidepressants. However, even for the most replicated findings there are inconsistent results, not only between studies, but also between the immune effects of the genetic variants and the resulting effects on depression. We find evidence that these discrepant findings may be explained, at least in part, by the heterogeneity of the depression immunophenotype, by environmental influences and gene × environment interactions, and by the complex interfacing of genetic variants with gene expression. Indeed, some of the most robust findings have been obtained in patients developing depression in the context of treatment with interferon-alpha, a widely used model to mimic depression in the context of inflammation. Further ‘omics’ approaches, through GWAS and transcriptomics, will finally shed light on the interaction between immune genes, their expression, and the influence of the environment, in the pathogenesis of depression.

Owing to the unique opportunity to assess individuals before and after they develop depression within a short timeframe, interferon-α (IFN-α) treatment for chronic hepatitis C virus (HCV) infection is an ideal model to identify molecular mechanisms relevant to major depression, especially in the context of enhanced inflammation. Fifty-eight patients were assessed prospectively, at baseline and monthly over 24 weeks of IFN-α treatment. New-onset cases of depression were determined using the Mini International Neuropsychiatric Interview (MINI). Whole-blood transcriptomic analyses were conducted to investigate the following: (1) baseline gene expression differences associated with future development of IFN-α-induced depression, before IFN-α, and (2) longitudinal gene expression changes from baseline to weeks 4 or 24 of IFN-α treatment, separately in those who did and did not develop depression. Transcriptomics data were analyzed using Partek Genomics Suite (1.4-fold, FDR adjusted p⩽0.05) and Ingenuity Pathway Analysis Software. Twenty patients (34%) developed IFN-α-induced depression. At baseline, 73 genes were differentially expressed in patients who later developed depression compared with those who did not. After 4 weeks of IFN-α treatment, 592 genes were modulated in the whole sample, representing primarily IFN-α-responsive genes. Substantially more genes were modulated only in patients who developed depression (n=506, compared with n=70 in patients who did not), with enrichment in inflammation-, neuroplasticity- and oxidative stress-related pathways. A similar picture was observed at week 24. Our data indicate that patients who develop IFN-α-induced depression have an increased biological sensitivity to IFN-α, as shown by larger gene expression changes, and specific signatures both as predictors and as correlates.

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.

SummaryIt is well established that the immune system can modulate brain functioning and influence behavioural processes. Awareness of communication between the immune and nervous systems has, over the years, progressively heightened interest in the relationship between psychiatric disorders and immune function. By reviewing findings from studies investigating inflammation in the periphery and in the central nervous systems, we summarise here the evidence linking inflammation to the development of depression, schizophrenia and bipolar disorder. We discuss how a pathophysiological role for inflammation has now been recognised across different psychiatric disorders, at least in a significant subpopulation of patients. Finally, we discuss a possible role for these findings in the development of future diagnostic classifications of psychiatric disorders as well as of new treatment strategies.

In the last few decades there has been a growing interest in the role of psychoneuroimmunological dysfunction in neuropsychiatric disorders. This article presents recent advances in the literature, from preclinical and clinical studies, suggesting that mood and anxiety disorders are, at least in part, conditions in which the inflammatory system is activated. The evidence-base comprises alterations in the peripheral immune systems of patients with mood or anxiety disorders, together with the development of depression- and anxiety-like symptoms induced by inflammatory agents. The reported anti-inflammatory effects of current psychotropic medications as well as the efficacy of anti-inflammatory medications in treating symptoms of depression and anxiety are also reviewed. Finally, potential mechanisms mediating the link between inflammation and symptomatology presented in these neuropsychiatric illnesses are discussed as well. In the last few decades there has been a growing interest in the role of psychoneuroimmunological dysfunction in neuropsychiatric disorders. This article presents recent advances in the literature, from preclinical and clinical studies, suggesting that mood and anxiety disorders are, at least in part, conditions in which the inflammatory system is activated. The evidence-base comprises alterations in the peripheral immune systems of patients with mood or anxiety disorders, together with the development of depression- and anxiety-like symptoms induced by inflammatory agents. The reported anti-inflammatory effects of current psychotropic medications as well as the efficacy of anti-inflammatory medications in treating symptoms of depression and anxiety are also reviewed. Finally, potential mechanisms mediating the link between inflammation and symptomatology presented in these neuropsychiatric illnesses are discussed as well. [[Psychiatr Ann. 2015;45(5):240–248.]

The risk of individuals having adverse effects from drug use (eg, alcohol) generally depends on the frequency of use and potency of the drug used. We aimed to investigate how frequent use of skunk-like (high-potency) cannabis in south London affected the association between cannabis and psychotic disorders.

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.

Despite its efficacy in treating hepatitis C, interferon- (IFN-) can cause depression. The purpose of this systematic review is to summarize and discuss the available and effective therapies in treating IFN-–induced depression.

The hypothalamus-pituitary-adrenal (HPA) axis is the endocrine axis most involved in the response to stress. Studies in first episode psychosis have recently reported raised levels of the stress hormones, cortisol and ACTH, and an increased volume of the pituitary gland, the main organ involved in the stress response. These findings suggest that first episode psychosis could be characterized by a hyperactivity of the HPA axis. These endocrine abnormalities could have important metabolic consequences for these patients, since activation of the stress hormonal system has been associated with increased intra-abdominal fat and impaired glucose tolerance. Increases in visceral or intra-abdominal fat distribution appear to be consistently associated with developing hyperinsulinemia, insulin resistance, dyslipidemia. Compared with the general population, patients with schizophrenia appear to suffer from higher rates of obesity-related illnesses such as impaired glucose tolerance, insulin resistance, type II diabetes mellitus and cardiovascular disease. This paper will review the evidence about HPA axis hyperactivity and metabolic abnormalities, and their possible link in first-episode psychosis.

Objective: Free fatty acids (FFAs) exert a stimulatory effect on the hypothalamic–pituitary–adrenal (HPA) axis in animals and inhibit spontaneous ACTH and cortisol secretion in humans. Patients with anorexia nervosa display concomitant HPA axis hyperactivity and increased lipolysis. We studied the effects of a lipid load on ACTH and cortisol secretion in patients with anorexia nervosa in comparison with normal subjects.Design: Eight women with anorexia nervosa (ANW; means ± s.e.m.: 23.9 ± 2.3 years of age; body mass index (BMI): 14.9 ± 0.6 kg/m2) and seven normal women (NW; 25.6 ± 2.3 years of age; BMI: 22.8 ± 1.9 kg/m2) had FFA, ACTH, cortisol, glucose and insulin levels measured in the morning every 30 min for 180 min during i.v. saline or lipid-heparin emulsion (LHE) infusion.Results: During saline infusion, ACTH and cortisol levels decreased spontaneously in both groups, ACTH and cortisol levels in ANW being higher than in NW. LHE infusion led to increased FFA levels in both groups (P< 0.005). The ACTH and cortisol decrease in NW was more marked than during saline infusion (P< 0.05). LHE infusion in ANW was associated with a more pronounced decrease in ACTH levels than during saline infusion (P< 0.05), while cortisol levels were unchanged. At the end of the LHE infusion, a progressive decrease in FFA levels was associated with an increase in ACTH and cortisol concentrations in NW (P< 0.05) but not in ANW in whom FFA levels decreased to a lesser extent (P< 0.05).Conclusions: This study showed that corticotroph sensitivity to the inhibitory effect of an FFA load is preserved in patients with anorexia nervosa, in spite of persistent adrenal hyperactivity.

Extensive research suggests a role for the innate immune system in the pathogenesis of depression, but most of the studies are conducted in adult populations, in high-income countries and mainly focus on the study of inflammatory proteins alone, which provides only a limited understanding of the immune pathways involved in the development of depression. The IDEA-FLAME study aims to identify immune phenotypes underlying increased risk of developing depression in adolescence in a middle-income country. To this end, we will perform deep-immunophenotyping of peripheral blood mononuclear cells and RNA genome-wide gene expression analyses in a longitudinal cohort of Brazilian adolescents stratified for depression risk. The project will involve the 3-year follow-up of an already recruited cohort of 150 Brazilian adolescents selected for risk/presence of depression on the basis of a composite risk score we developed using sociodemographic characteristics (50 adolescents with low-risk and 50 with high-risk of developing depression, and 50 adolescents with a current major depressive disorder). We will 1) test whether the risk group classification at baseline is associated with differences in immune cell frequency, phenotype and functional status, 2) test whether baseline immune markers (cytokines and immune cell markers) are associated with severity of depression at 3-year follow-up, and 3) identify changes in gene expression of immune pathways over the 3-year follow-up in adolescents with increased risk and presence of depression. Because of the exploratory nature of the study, the findings would need to be replicated in a separate and larger sample. Ultimately, this research will contribute to elucidating key immune therapeutic targets and inform the development of interventions to prevent onset of depression among adolescents.

Inflammatory processes in the Central Nervous System (CNS) have been proposed to mediate the association between peripheral inflammation and the development of psychiatric disorders, but we currently lack sensitive measures of CNS inflammation for human studies in vivo. Here we used quantitative MRI (qMRI) to explore the in vivocentral response to a peripheral immune challenge in healthy humans, and we assessed whether changes in quantitative relaxometry MRI parameters were associated with changes in peripheral inflammation.