Peripheral NF-κB dysregulation in people with schizophrenia drives inflammation: putative anti-inflammatory functions of NF-κB kinases

Elevations in plasma levels of pro-inflammatory cytokines and C-reactive protein (CRP) in patient blood have been associated with impairments in cognitive abilities and more severe psychiatric symptoms in people with schizophrenia. The transcription factor nuclear factor kappa B (NF-κB) regulates the gene expression of pro-inflammatory factors whose protein products trigger CRP release. NF-κB activation pathway mRNAs are increased in the brain in schizophrenia and are strongly related to neuroinflammation. Thus, it is likely that this central immune regulator is also dysregulated in the blood and associated with cytokine and CRP levels. We measured levels of six pro-inflammatory cytokine mRNAs and 18 mRNAs encoding NF-κB pathway members in peripheral blood leukocytes from 87 people with schizophrenia and 83 healthy control subjects. We then assessed the relationships between the alterations in NF-κB pathway genes, pro-inflammatory cytokine and CRP levels, psychiatric symptoms and cognition in people with schizophrenia. IL-1β and IFN-γ mRNAs were increased in patients compared to controls (both p < 0.001), while IL-6, IL-8, IL-18, and TNF-α mRNAs did not differ. Recursive two-step cluster analysis revealed that high levels of IL-1β mRNA and high levels of plasma CRP defined ‘high inflammation’ individuals in our cohort, and a higher proportion of people with schizophrenia were identified as displaying ‘high inflammation’ compared to controls using this method (p = 0.03). Overall, leukocyte expression of the NF-κB-activating receptors, TLR4 and TNFR2, and the NF-κB subunit, RelB, was increased in people with schizophrenia compared to healthy control subjects (all p < 0.01), while NF-κB-inducing kinase mRNAs IKKβ and NIK were downregulated in patients (all p < 0.05). We found that elevations in TLR4 and RelB appear more related to inflammatory status than to a diagnosis of schizophrenia, but changes in TNFR2 occur in both the high and low inflammation patients (but were exaggerated in high inflammation patients). Further, decreased leukocyte expression of IKKβ and NIK mRNAs was unique to high inflammation patients, which may represent schizophrenia-specific dysregulation of NF-κB that gives rise to peripheral inflammation in a subset of patients.

Genetic liability to rheumatoid arthritis on autism and autistic traits: polygenic risk score and Mendelian randomization analyses

Higher prevalence of autism in offspring born to mothers with rheumatoid arthritis has been reported in observational studies. We investigated (a) the associations between maternal and offspring’s own genetic liability for rheumatoid arthritis and autism-related outcomes in the offspring using polygenic risk scores (PRS) and (b) whether the effects were causal using Mendelian randomization (MR). Using the latest genome-wide association (GWAS) summary data on rheumatoid arthritis and individual-level data from the Avon Longitudinal Study of Parents and Children, United Kingdom, we constructed PRSs for maternal and offspring genetic liability for rheumatoid arthritis (single-nucleotide polymorphism [SNP] p-value threshold 0.05). We investigated associations with autism, and autistic traits: social and communication difficulties, coherence, repetitive behaviours and sociability. We used modified Poisson regression with robust standard errors. In two-sample MR analyses, we used 40 genome-wide significant SNPs for rheumatoid arthritis and investigated the causal effects on risk for autism, in 18,381 cases and 27,969 controls of the Psychiatric Genetics Consortium and iPSYCH. Sample size ranged from 4992 to 7849 in PRS analyses. We found little evidence of associations between rheumatoid arthritis PRSs and autism-related phenotypes in the offspring (maternal PRS on autism: RR 0.89, 95%CI 0.73–1.07, p = 0.21; offspring’s own PRS on autism: RR 1.11, 95%CI 0.88–1.39, p = 0.39). MR results provided little evidence for a causal effect (IVW OR 1.01, 95%CI 0.98–1.04, p = 0.56). There was little evidence for associations between genetic liability for rheumatoid arthritis on autism-related outcomes in offspring. Lifetime risk for rheumatoid arthritis has no causal effects on autism.

Risk for opioid misuse in chronic pain patients is associated with endogenous opioid system dysregulation

Abstractµ-Opioid receptors (MOR) are a major target of endogenous and exogenous opioids, including opioid pain medications. The µ-opioid neurotransmitter system is heavily implicated in the pathophysiology of chronic pain and opioid use disorder and, as such, central measures of µ-opioid system functioning are increasingly being considered as putative biomarkers for risk to misuse opioids. To explore the relationship between MOR system function and risk for opioid misuse, 28 subjects with chronic nonspecific back pain completed a clinically validated measure of opioid misuse risk, the Pain Medication Questionnaire (PMQ), and were subsequently separated into high (PMQ > 21) and low (PMQ ≤ 21) opioid misuse risk groups. Chronic pain patients along with 15 control participants underwent two separate [11C]-carfentanil positron emission tomography scans to explore MOR functional measures: one at baseline and one during a sustained pain-stress challenge, with the difference between the two providing an indirect measure of stress-induced endogenous opioid release. We found that chronic pain participants at high risk for opioid misuse displayed higher baseline MOR availability within the right amygdala relative to those at low risk. By contrast, patients at low risk for opioid misuse showed less pain-induced activation of MOR-mediated, endogenous opioid neurotransmission in the nucleus accumbens. This study links human in vivo MOR system functional measures to the development of addictive disorders and provides novel evidence that MORs and µ-opioid system responsivity may underlie risk to misuse opioids among chronic pain patients.

Imbalance between default mode and sensorimotor connectivity is associated with perseverative thinking in obsessive-compulsive disorder

Obsessive-compulsive disorder (OCD) is highly heterogeneous. Although perseverative negative thinking (PT) is a feature of OCD, little is known about its neural mechanisms or relationship to clinical heterogeneity in the disorder. In a sample of 85 OCD patients, we investigated the relationships between self-reported PT, clinical symptom subtypes, and resting-state functional connectivity measures of local and global connectivity. Results indicated that PT scores were highly variable within the OCD sample, with greater PT relating to higher severity of the “unacceptable thoughts” symptom dimension. PT was positively related to local connectivity in subgenual anterior cingulate cortex (ACC), pregenual ACC, and the temporal poles—areas that are part of, or closely linked to, the default mode network (DMN)—and negatively related to local connectivity in sensorimotor cortex. While the majority of patients showed higher local connectivity strengths in sensorimotor compared to DMN regions, OCD patients with higher PT scores had less of an imbalance between sensorimotor and DMN connectivity than those with lower PT scores, with healthy controls exhibiting an intermediate pattern. Clinically, this imbalance was related to both the “unacceptable thoughts” and “symmetry/not-just-right-experiences” symptom dimensions, but in opposite directions. These effects remained significant after accounting for variance related to psychiatric comorbidity and medication use in the OCD sample, and no significant relationships were found between PT and global connectivity. These data indicate that PT is related to symptom and neural variability in OCD. Future work may wish to target this circuity when developing personalized interventions for patients with these symptoms.

Fibroblast growth factor 21 (FGF21) is increased in MDD and interacts with body mass index (BMI) to affect depression trajectory

Fibroblast growth factor 21 (FGF21) is a key regulator of metabolic function and nutrient preference. It also affects biological pathways associated with major depressive disorder (MDD), including corticotrophin-releasing hormone (CRH), leptin, and sympathetic activity. Lower levels of cerebrospinal fluid FGF21 have been associated with higher Beck Depression Inventory scores. FGF21 was examined as a metabolic marker that could be associated with MDD and evaluated as a biomarker of antidepressant treatment response in a large, randomized placebo-controlled trial in chronic, early-onset MDD participants. FGF21 levels at baseline and during treatment were determined for participants in the Establishing Moderators and Biosignatures of Antidepressant Response for Clinical Care (EMBARC) study. FGF21 was analyzed by ELISA in individuals with chronic, early-onset MDD (first major depressive episode before 30 years) compared to healthy control participants. Participants with MDD had higher levels of FGF21 compared to healthy controls (HCs), even after controlling for baseline age, sex, race, Hispanic ethnicity, BMI, and site (β-coefficient = 1.20, p < 0.0001, Cohen’s d = 0.60). FGF21 did not change over time nor differ between treatment groups. Interestingly though, those with normal BMI and lower FGF21 levels showed a reduction in depression severity over time compared to all other groups. In conclusion, depression is associated with higher levels of FGF21 compared to healthy controls and those with lower levels of FGF21 (25th percentile of the sample) in the context of normal-weight BMI seem to have improved depression severity over time.

Associations between genetic loci, environment factors and mental disorders: a genome-wide survival analysis using the UK Biobank data

It is well-accepted that both environment and genetic factors contribute to the development of mental disorders (MD). However, few genetic studies used time-to-event data analysis to identify the susceptibility genetic variants associated with MD and explore the role of environment factors in these associations. In order to detect novel genetic loci associated with MD based on the time-to-event data and identify the role of environmental factors in them, this study recruited 376,806 participants from the UK Biobank cohort. The MD outcomes (including overall MD status, anxiety, depression and substance use disorders (SUD)) were defined based on in-patient hospital, self-reported and death registry data collected in the UK Biobank. SPACOX approach was used to identify the susceptibility loci for MD using the time-to-event data of the UK Biobank cohort. And then we estimated the associations between identified candidate loci, fourteen environment factors and MD through a phenome-wide association study and mediation analysis. SPACOX identified multiple candidate loci for overall MD status, depression and SUD, such as rs139813674 (P value = 8.39 × 10–9, ZNF684) for overall MD status, rs7231178 (DCC, P value = 2.11 × 10–9) for depression, and rs10228494 (FOXP2, P value = 6.58 × 10–10) for SUD. Multiple environment factors could influence the associations between identified loci and MD, such as confide in others and felt hated. Our study identified novel candidate loci for MD, highlighting the strength of time-to-event data based genetic association studies. We also observed that multiple environment factors could influence the association between susceptibility loci and MD.

Immunological causes of obsessive-compulsive disorder: is it time for the concept of an “autoimmune OCD” subtype?

Obsessive-compulsive disorder (OCD) is a highly disabling mental illness that can be divided into frequent primary and rarer organic secondary forms. Its association with secondary autoimmune triggers was introduced through the discovery of Pediatric Autoimmune Neuropsychiatric Disorder Associated with Streptococcal infection (PANDAS) and Pediatric Acute onset Neuropsychiatric Syndrome (PANS). Autoimmune encephalitis and systemic autoimmune diseases or other autoimmune brain diseases, such as multiple sclerosis, have also been reported to sometimes present with obsessive-compulsive symptoms (OCS). Subgroups of patients with OCD show elevated proinflammatory cytokines and autoantibodies against targets that include the basal ganglia. In this conceptual review paper, the clinical manifestations, pathophysiological considerations, diagnostic investigations, and treatment approaches of immune-related secondary OCD are summarized. The novel concept of “autoimmune OCD” is proposed for a small subgroup of OCD patients, and clinical signs based on the PANDAS/PANS criteria and from recent experience with autoimmune encephalitis and autoimmune psychosis are suggested. Red flag signs for “autoimmune OCD” could include (sub)acute onset, unusual age of onset, atypical presentation of OCS with neuropsychiatric features (e.g., disproportionate cognitive deficits) or accompanying neurological symptoms (e.g., movement disorders), autonomic dysfunction, treatment resistance, associations of symptom onset with infections such as group A streptococcus, comorbid autoimmune diseases or malignancies. Clinical investigations may also reveal alterations such as increased levels of anti-basal ganglia or dopamine receptor antibodies or inflammatory changes in the basal ganglia in neuroimaging. Based on these red flag signs, the criteria for a possible, probable, and definite autoimmune OCD subtype are proposed.

Reward and aversion encoding in the lateral habenula for innate and learned behaviours

Throughout life, individuals experience a vast array of positive and aversive events that trigger adaptive behavioural responses. These events are often unpredicted and engage actions that are likely anchored on innate behavioural programs expressed by each individual member of virtually all animal species. In a second step, environmental cues, that are initially neutral, acquire value through the association with external sensory stimuli, and become instrumental to predict upcoming positive or negative events. This process ultimately prompts learned goal-directed actions allowing the pursuit of rewarding experience or the avoidance of a danger. Both innate and learned behavioural programs are evolutionarily conserved and fundamental for survival. Among the brain structures participating in the encoding of positive/negative stimuli and contributing to innate and learned behaviours is the epithalamic lateral habenula (LHb). The LHb provides top-down control of monoaminergic systems, responds to unexpected appetitive/aversive stimuli as well as external cues that predict the upcoming rewards or punishments. Accordingly, the LHb controls a number of behaviours that are innate (originating from unpredicted stimuli), and learned (stemming from predictive cues). In this review, we will discuss the progresses that rodent’s experimental work made in identifying how LHb activity governs these vital processes, and we will provide a view on how these findings integrate within a complex circuit connectivity.

Prenatal origins of suicide mortality: A prospective cohort study in the United States

Most suicide research focuses on acute precipitants and is conducted in high-risk populations. Yet, vulnerability to suicide is likely established years prior to its occurrence. In this study, we aimed to investigate the risk of suicide mortality conferred by prenatal sociodemographic and pregnancy-related factors. Offspring of participants (N = 49,853) of the Collaborative Perinatal Project, a U.S. population-based cohort of pregnancies enrolled between 1959 and 1966, were linked to the U.S. National Death Index to determine their vital status by the end 2016. We examined associations between sociodemographic factors during pregnancy, pregnancy complications, labor and delivery complications, and neonatal complications with suicide death coded according to ICD-9/10 criteria. By the end of 2016, 3,555 participants had died. Of these, 288 (214 males, 74 females) died by suicide (incidence rate = 15.6 per 100,000 person-years, 95% Confidence Interval [CI] = 13.9–17.5). In adjusted models, male sex (Hazard Ratio [HR] = 2.98, CI: 2.26–3.93), White race (HR = 2.14, CI = 1.63–2.83), low parental education (HR = 2.23, CI = 1.38–3.62), manual parental occupation (HR = 1.38, CI = 1.05–1.82), being a younger sibling (HR = 1.52, CI = 1.10–2.11), higher rates of pregnancy complications (HR = 2.36, CI = 1.08–5.16), and smoking during pregnancy (HR = 1,28, CI = 0.99–1.66) were independently associated with suicide risk, whereas birth and neonatal complications were not. Consistent with the developmental origins of psychiatric disorders, vulnerability to suicide mortality is established early in development. Both sociodemographic and pregnancy factors play a role in this risk, which underscores the importance of considering life course approaches to suicide prevention, possibly including provision of high-quality prenatal care, and alleviating the socioeconomic burdens of mothers and families.

Comprehensive exploration of the genetic contribution of the dopaminergic and serotonergic pathways to psychiatric disorders

Psychiatric disorders are highly prevalent and display considerable clinical and genetic overlap. Dopaminergic and serotonergic neurotransmission have been shown to play an important role in many psychiatric disorders. Here we aim to assess the genetic contribution of these systems to eight psychiatric disorders (attention-deficit hyperactivity disorder (ADHD), anorexia nervosa (ANO), autism spectrum disorder (ASD), bipolar disorder (BIP), major depression (MD), obsessive-compulsive disorder (OCD), schizophrenia (SCZ) and Tourette’s syndrome (TS)) using publicly available GWAS analyses performed by the Psychiatric Genomics Consortium that include more than 160,000 cases and 275,000 controls. To do so, we elaborated four different gene sets: two ‘wide’ selections for dopamine (DA) and for serotonin (SERT) using the Gene Ontology and KEGG pathways tools, and two’core’ selections for the same systems, manually curated. At the gene level, we found 67 genes from the DA and/or SERT gene sets significantly associated with one of the studied disorders, and 12 of them were associated with two different disorders. Gene-set analysis revealed significant associations for ADHD and ASD with the wide DA gene set, for BIP with the wide SERT gene set, and for MD with the core SERT set. Interestingly, interrogation of a cross-disorder GWAS meta-analysis of the eight psychiatric conditions displayed association with the wide DA gene set. To our knowledge, this is the first systematic examination of genes encoding proteins essential to the function of these two neurotransmitter systems in these disorders. Our results support a pleiotropic contribution of the dopaminergic and serotonergic systems in several psychiatric conditions.