Hikikomori is a severe pathological form of social withdrawal that first emerged in Japan in the late 20th century and has since become a global phenomenon. This was recently added to the cultural concept of distress in the DSM-5-TR.

This study aimed to examine the precise network structure of social withdrawal symptoms in Asian psychiatric patients at high risk of hikikomori using data from Phase 3 of the Research on Asian Psychotropic Prescription Patterns for Antidepressants.

High risk of hikikomori was defined as a score ≥ 42 on the 1-month version of the 25-item Hikikomori Questionnaire (HQ-25M), a scale that measures social withdrawal symptoms. The HQ-25M network structures were estimated separately for patients at high and low risks of hikikomori. The differences in network structure invariance and global strength invariance between the two networks were evaluated. Data from 2993 participants were assessed, including 1939 and 1054 patients at high and low risk of hikikomori, respectively.

Network analysis revealed that enjoyment of social activities was the most central symptom among patients at high risk of hikikomori, whereas trust issues were the most central among those at low risk of hikikomori. In addition, although no significant differences were identified in the overall network structures, the global strength invariance differed significantly between networks.

While the study has several limitations, the findings may point to potential differences in how social withdrawal symptoms are structured between individuals with high versus low risk of hikikomori, particularly with regard to the overall connectivity among symptoms. A notable finding is that low enjoyment of social interactions may be a main area for early intervention. However, given that the participants were all psychiatric patients receiving antidepressant medication and able to attend in-person evaluations, the applicability of these results to non-clinical groups or individuals with more severe social withdrawal may be restricted.

Physical activity is a modifiable risk factor for dementia. However, the potential reverse effect of adverse cognitive change on physical activity remains underexplored.

Cross-sectional analysis of a subset of National Health and Aging Trends Study (NHATS; N = 706) U.S. Medicare beneficiaries. Dementia status (dementia vs. no dementia) was classified per NHATS protocol. Cognitive performance was assessed in executive function, orientation, and memory domains. Daily physical activity was assessed using wrist-worn accelerometers (Actigraph Insight).

Compared with participants living without dementia, participants living with dementia had lower daily activity counts (×1000) (-319.3; 95% confidence interval (CI), -471.0 - -167.5), lower activity intensity (-1129.2 maximum counts per day; 95% CI, -1518.4 - -740.0 counts per day), less time spent active (64.3 min/day; 95% CI, 28.1-100.4 min/day), and more fragmented patterns of activity (6.1%; 95% CI, 3.0%-9.2%). One-unit higher cognitive performance in executive function was associated with higher daily activity counts (×1000) (67.9; 95% CI, 19.7-116.0), higher activity intensity (375.4; 95% CI, 232.0-518.7), more time spent active (12.4 min; 95% CI, 2.1-22.7 min), and lower fragmentation (-1.4%; 95% CI, -2.2% - -0.5%). One-unit higher orientation score was associated with higher daily activity counts (×1000) (61.0; 95% CI, 31.9-90.0), higher activity intensity (266.6; 95% CI, 197.9-335.2), more time spent active (11.6 min; 95% CI, 5.2-18.0 more active minutes), greater stability of daily activities (1.1; 95% CI, 0.3-1.9), and lower fragmentation (-1.2%; 95% CI, -1.7% - -0.7%). One-unit higher memory score was associated with higher daily activity counts (×1000) (28.1; 95% CI, 15.0-41.2), higher activity intensity (113.5; 95% CI, 77.0-150.1), and more time spent active (5.2 min; 95% CI, 2.4-8.0 min), as well as lower fragmentation (-0.5%; 95% CI, -0.7% - -0.3%).

In a nationally representative sample of older US adults, dementia and lower cognitive performance were associated with lower volume and intensity of daily physical activity, as well as more fragmented and less consistent patterns of physical activity. These associations emphasize the need for considering the impact of cognition on individuals' ability to engage in and maintain regular physical activity and suggest shifts in daily quantities and patterns of activity consistent with cognitive decline and dementia.

The authors sought to determine whether an inflammatory challenge with lipopolysaccharide (LPS) differentially impacts symptoms of anhedonia in participants with major depressive disorder with high (≥3 mg/L) and low (≤1.5 mg/L) serum C-reactive protein (CRP) concentrations.

Sixty-eight participants with major depressive disorder were randomly assigned, in a 1:1 ratio, to receive LPS (0.8 ng/kg body weight) or placebo (saline) in a parallel-group double-blind design. Participants were stratified according to baseline CRP concentrations, yielding four groups: high-CRP LPS (N=13), low-CRP LPS (N=19), high-CRP placebo (N=13), and low-CRP placebo (N=19). Blood was sampled at baseline, at 1, 1.5, 3.5, 6, and 24 hours, and 1 week after LPS or saline administration, with concurrent assessment of psychological outcomes. The primary outcome measure was the Snaith-Hamilton Pleasure Scale (SHAPS), and the primary contrast of interest was the change between baseline and 1.5 hours (peak of the inflammatory response) in the high-CRP versus low-CRP groups receiving LPS. Secondary outcomes included the Montgomery-Åsberg Depression Rating Scale (MADRS) and serum levels of three cytokines: interleukin-6 (IL-6), IL-10, and tumor necrosis factor (TNF). Data were analyzed with linear mixed models.

Significantly greater increases in self-reported anhedonia (on the SHAPS) and IL-6 levels were observed between baseline and 1.5 hours in the high-CRP versus low-CRP LPS groups. There were no significant differences for TNF and IL-10. The MADRS was not administered at 1.5 hours; secondary analyses showed a significant group-by-condition-by-time interaction driven by a greater decrease in MADRS scores between baseline and 24 hours in the high-CRP group.

Depressed individuals with systemic inflammation appeared to be biologically primed to respond more strongly to inflammatory stimuli, and psychologically, this sensitization impacted the symptom of anhedonia, the primary outcome.

Older adults spend the majority of their day engaging in sedentary behavior, which increases risk of mortality by 22%. Despite the well-established health benefits of physical activity, a large portion of older adults remain sedentary. Recent evidence suggests that inflammation contributes to lack of motivation, which is a critical barrier to overcoming sedentary behavior in older adults. Given that inflammation is highly modifiable by diet, an anti-inflammatory dietary strategy may be a viable way to improve inflammation-driven lack of motivation and ultimately increase physical activity in sedentary older adults. However, interventions targeting such a pathway are scarce. We propose a study intervention protocol, which aims to determine the feasibility and preliminary efficacy of daily supplementation of freeze-dried blueberries. Supplementation with blueberries provides 2 anti-inflammatory nutrients (fiber and anthocyanins) to theoretically reduce inflammation-driven lack of motivation and thereby enhance physical activity in older adults with sedentary behavior and mild depressive symptoms.

The current study is planned as a single-site, randomized, double-blind, parallel pilot study in 40 older adults with sedentary behavior and mild depressive symptoms. Individuals with depressive symptoms often lack motivation and have increased levels of inflammatory cytokines, representing an ideal population for an anti-inflammatory dietary intervention to improve motivation. Participants will be randomized to consume either 48 g of freeze-dried blueberry powder (~ 600 mg of anthocyanins and ~ 8 g of fiber) or a nutritionally matched placebo powder (without any known amounts of anthocyanins and fiber) each day for a total of 12 weeks.

Identification of a dietary intervention to target the inflammatory pathways may offer a novel and feasible approach to increase motivation and engagement of physical activity in older adults. If feasible and effective, such a strategy would help avoid the plethora of health consequences associated with sedentary behavior and physical inactivity.

The current study is approved by the Advarra IRB (#Pro00064749) and registered at Clinicaltrials.gov (Identifier: NCT05735587).

Inflammation is associated with a range of neuropsychiatric symptoms, but the issue of causality remains unclear. We used complementary non-genetic, genetic risk score (GRS), and Mendelian randomization (MR) analyses to examine whether inflammatory markers are associated with affect, depressive and anxiety disorders, and cognition. We tested in ≈55,098 (59% female) individuals from the Dutch Lifelines cohort the concurrent/prospective associations of C-reactive protein (CRP) with: depressive and anxiety disorders; positive/negative affect; and attention, psychomotor speed, episodic memory, and executive functioning at baseline and a follow-up assessment occurring 3.91 years later (SD = 1.21). Additionally, we examined the association between inflammatory GRSs (CRP, interleukin-6 [IL-6], IL-6 receptor [IL-6R and soluble IL-6R (sIL-6R)], glycoprotein acetyls [GlycA]) on these same outcomes (Nmin = 35,300; Nmax = 57,946), followed by MR analysis examining evidence of causality of CRP on outcomes (Nmin=22,154; Nmax = 23,268). In non-genetic analyses, higher CRP was associated with depressive disorder, lower positive/higher negative affect, and worse executive function, attention, and psychomotor speed after adjusting for potential confounders. In genetic analyses, CRPGRS was associated with any anxiety disorder (β = 0.002, p = 0.037) whereas GlycAGRS was associated with major depressive disorder (β = 0.001, p = 0.036). Both CRPGRS (β = 0.006, p = 0.035) and GlycAGRS (β = 0.006, p = 0.049) were associated with greater negative affect. Inflammatory GRSs were not associated with cognition, except sIL-6RGRS which was associated with poorer memory (β = -0.009, p = 0.018). There was a non-significant CRP-anxiety association using MR (β = 0.12; p = 0.054). Genetic and non-genetic analyses provide consistent evidence for an association between CRP and negative affect. These results suggest that inflammation may impact a broad range of trans-diagnostic affective symptoms.

Psychiatric disorders and internal diseases frequently co-occur, posing significant challenges due to overlapping symptoms, shared pathophysiological mechanisms, and increased healthcare burdens. Neuroinflammation has emerged as a central mechanism linking these conditions, driven by systemic inflammation, hypothalamic-pituitary-adrenal (HPA) axis dysregulation, and autonomic nervous system (ANS) imbalance. This review synthesizes current evidence on the role of neuroinflammation in comorbid conditions such as depression, anxiety, cardiovascular disease, and diabetes mellitus, emphasizing bidirectional relationships and shared inflammatory pathways. This analysis identifies gaps in longitudinal studies, biomarker validation, and the integration of multidisciplinary care models. Emerging therapeutic approaches, including IL-6 inhibitors, vagus nerve stimulation, and behavioral interventions, show promise but remain underexplored in combined applications. Furthermore, disparities in research representation limit the generalizability of findings and highlight the need for inclusive clinical trials. Addressing these gaps through precision medicine, advanced biomarker monitoring technologies, and equitable healthcare strategies could transform the management of these complex comorbidities. By advancing our understanding of neuroinflammatory mechanisms and promoting integrated interventions, this review underscores the need for a collaborative, patient-centered approach to improve outcomes and reduce the global burden of psychiatric and internal disease comorbidities.

Non-suicidal self-injury (NSSI) in adolescent depression is a prevalent and clinically significant behavior linked to dysregulated peripheral inflammation and corticostriatal circuitry dysfunction. However, the neuroimmune mechanisms bridging these systems remain poorly understood. Here, we combined peripheral cytokine profiling with static/dynamic functional connectivity (sFC/dFC) analysis to investigate the potential influence of inflammaton on corticostriatal circuit related to NSSI. A set of peripheral blood inflammatory markers and resting-state functional magnetic resonance imaging (rs-fMRI) were collected in depression with NSSI (NSSI+), depression without NSSI (NSSI-), and healthy controls (HC). We first ascertain group differences in level of pro- and anti-inflammatory cytokines. And using ventral/dorsal striatal seeds, we compared whole-brain, voxel-wise sFC and dFC differences across three groups. Further, we tested the mediation effects of connectivity in the association between inflammatory markers and NSSI frequency. NSSI+ group exhibited elevated pro-inflammatory cytokines (C-reactive protein (CRP), interleukin (IL)-1, and IL-6) whereas reduced anti-inflammatory cytokines (IL-10), compared to NSSI- and HC. Neuroimaging analysis revealed corticostriatal dysconnectivity mainly characterized by static hyperconnectivity between dorsal striatum and thalamus, dynamic instability in dorsal striatum-lingual pathways, and dynamic rigidity in ventral striatum-prefrontal/temporal/occipital gyrus circuits. Critically, sFC of dorsal striatum-thalamus and dFC of dorsal striatum-lingual gyrus mediated the prospective association between altered CRP and NSSI frequency, establishing corticostriatal circuits as conduits for inflammatory effects on NSSI. By bridging molecular psychiatry with circuit neuroscience, this work advances precision management of NSSI in adolescent depression, prioritizing biomarker-driven strategies to disrupt neuroimmune maladaptation.

In light of the intricate nature of animal behavior regulation, a theoretical model is proposed, grounded in the COM-B (Capability, Opportunity, Motivation - Behavior) framework, which has gained considerable traction in the domain of human behavioral intervention. When extending the COM-B model to behavioral neuroscience, we first discuss the utility of the model in animal research, particularly its capacity to integrate environmental and social factors, and enhance cross-species comparisons, including animal-to-human translations and evolutionary considerations. The subsequent discussion then summarizes the advantages of utilizing the COM-B model in neuroscience are summarized, including the facilitation of a systems-level understanding of behavior and the establishment of a link between neural mechanisms and specific behavioral components. The experimental design for the application of the COM-B model in neuroscience is proposed to elucidate the brain regulatory processes that govern behavior. Finally, three specific examples are provided to illustrate the theoretical considerations, namely feeding and social behavior, and the role of neuromodulators in the control of behavior.

Chronic, low-grade inflammation has been associated with motivational deficits in patients with major depression (MD). In turn, impaired motivation has been linked to poor quality of life across psychiatric disorders. We thus determined effects of the anti-inflammatory drug infliximab-a potent tumor necrosis factor (TNF) antagonist-on behavioral and neural measures of motivation in 42 medically stable, unmedicated MD patients with a C-reactive protein >3 mg/L. All patients underwent a double-blind, placebo-controlled, single-dose, randomized clinical trial with infliximab (5 mg/kg) versus placebo. Behavioral performance on an effort-based decision-making task, self-report questionnaires, and neural responses during event-related functional magnetic resonance imaging were assessed at baseline and 2 weeks following infusion. We found that relative to placebo, patients receiving infliximab were more willing to expend effort for rewards. Moreover, increase in effortful choices was associated with reduced TNF signaling as indexed by decreased soluble TNF receptor type 2 (sTNFR2). Changes in effort-based decision-making and sTNFR2 were also associated with changes in task-related activity in a network of brain areas, including dorsomedial prefrontal cortex (dmPFC), ventral striatum, and putamen, as well as the functional connectivity between these regions. Changes in sTNFR2 also mediated the relationships between drug condition and behavioral and neuroimaging measures. Finally, changes in self-reported anhedonia symptoms and effort-discounting behavior were associated with greater responses of an independently validated whole-brain predictive model (aka "neural signature") sensitive to monetary rewards. Taken together, these data support the use of anti-inflammatory treatment to improve effort-based decision-making and associated brain circuitry in depressed patients with high inflammation.

Acute stress has enduring effects on the brain and motivated behavior across species. For example, acute stress produces persisting decreases in voluntary physical activity as well as molecular changes in the striatum, a brain region that regulates voluntary physical activity and other motivated behaviors. Microglia, the primary immune cells of the central nervous system, are positioned at the interface between neural responses to stress and neural coordination of voluntary activity in that they respond to stress, sense molecular changes in the striatum, and modulate neuronal activity. However, the role of striatal microglia in stress-induced long-term suppression of voluntary activity is unknown. Here, we employ single-nucleus RNA sequencing to investigate how stress and exercise impact the biology of microglia in the striatum. We find that striatal microglia display altered activation profiles 6 weeks after an acute stressor. Furthermore, we show that access to a running wheel is associated with an additional and distinct microglial activation profile characterized by upregulation of genes related to complement components and phagocytosis pathways. Finally, we find that distinct gene sets show expression changes associated with general access to a running wheel versus variation in running levels. Taken together, our results deepen our understanding of the diverse molecular states that striatal microglia assume in response to stress and exercise and suggest that microglia exhibit a broader range of functional states than previously thought.

The gene CELSR3 (Cadherin EGF LAG Seven-pass-G-type Receptor 3) has been recently recognized as a high-confidence risk factor for Tourette syndrome (TS). Additionally, Celsr3 mutant mice have been reported to exhibit TS-related behaviors and increased dopamine release in the striatum. Building on these findings, we further characterized the neurobehavioral and molecular profile of Celsr3 mutant mice to understand better the biological mechanisms connecting the deficiency of this gene and TS-related phenotypes. Our analyses confirmed that Celsr3 mutant mice displayed grooming stereotypies and tic-like jerks, as well as sensorimotor gating deficits, which were opposed by TS therapies. Spatial transcriptomic analyses revealed widespread extracellular matrix abnormalities in the striatum of Celsr3 mutants. Single-nucleus transcriptomics also showed significant upregulation of the Drd3 gene, encoding the dopamine D3 receptor, in striosomal D1-positive neurons. In situ hybridization and immunofluorescence confirmed dysregulated D3 receptor expression, with lower levels in presynaptic striatal fibers and higher levels in striatal D1-positive neurons. Activating and blocking D3 receptors amplified or decreased tic-like jerks and stereotypies in Celsr3-deficient mice, respectively. These findings suggest that modifications of D3 receptor distribution contribute to the tic-like responses associated with Celsr3 deficiency.

Although MK801-induced NMDA receptor (NMDAR) hypofunction mimics schizophrenia symptoms, the exact factors causing NMDAR inhibition are unknown. Unexpectedly, external stress elicits formaldehyde (FA) generation; FA can induce depression and cognitive impairments by blocking NMDARs. This study explores using FA injection to establish a schizophrenia-like model in mice. Here, we reported that external stress-derived FA induces schizophrenia-like behaviors. Four experimental methods were used to induce schizophrenia-like symptoms in wild-type mice: double electrode stimulation of the ventral tegmental area (VTA), microinjection of FA or tetrahydroisoquinoline (TIQ) into the VTA, and intraperitoneal injection of MK801. Then the metabolic levels of FA and dopamine (DA) in the prefrontal cortex (PFC) and VTA were quantified using ELISA kits. We found that external stress-electrical stimulation via VTA caused schizophrenia-like behaviors, including despairing behavior as measured by the tail suspension test, anhedonia as evaluated by the sucrose preference test, stereotypical behavior as assessed by the marble burying test (MBT), anxiety-like behavior as measured by the open-field test and memory deficit as detected by the Y-maze. These behaviors correlated with increased DA and TIQ levels in the VTA and decreased DA levels in the PFC. High-resolution mass spectrometry (HRMS) and high-performance liquid chromatography (HPLC) confirmed TIQ formation from FA and DA. Furthermore, injecting TIQ into the VTA induced schizophrenia-like symptoms in mice, marked by higher FA and lower DA levels in the PFC than control mice. Strikingly, injecting FA into the VTA as well as administering MK-801 induced schizophrenia-like behaviors associated with reduced DA levels and low activity of tyrosine hydroxylase (TH) and monoamine oxidase (MAO) in the PFC. Hence, microinfusion of FA into the VTA can be used to prepare schizophrenia-like changes mouse model, suggesting that stress-derived FA may act as an endogenous trigger of schizophrenia-like changes.

The biopsychosocial model suggests that temporomandibular disorders (TMDs) often coexist with mental health disorders, particularly depression and anxiety, affecting a significant portion of the global population. The interplay between TMDs and mental health disorders contributes to a complex comorbidity, perpetuating a cycle of mutual influence and reinforcement. This review investigates the neurobiological mechanisms and epidemiological evidence supporting the shared etiology of TMDs and mental health disorders, exploring potential shared vulnerabilities and bidirectional causal relationships. Shared vulnerabilities between TMDs and mental health disorders may stem from genetic and epigenetic predispositions, psychosocial factors, and behavioral aspects. Inflammatory cytokines, neurotransmitters, neurotrophins, and neuropeptides play pivotal roles in both peripheral and central sensitization as well as neuroinflammation. Brain imaging studies suggest that TMDs and mental health disorders exhibit overlapping brain regions indicative of reward processing deficits and anomalies within the triple network model. Future research efforts are crucial for developing a comprehensive understanding of the underlying mechanisms and confirming the reciprocal causal effects between TMDs and mental health disorders. This review provides valuable insights for oral healthcare professionals, stressing the importance of optimizing treatment strategies for individuals dealing with concurrent TMDs and mental health issues through a personalized, holistic, and multidisciplinary approach.

Major depressive disorder is a significant global cause of disability, particularly among adolescents. The dopamine system and nearby neuroinflammation, crucial for regulating mood and processing rewards, are central to the frontostriatal circuit, which is linked to depression. This study aimed to investigate the effect of post-weaning isolation (PWI) on depression in adolescent mice, with a focus on exploring the involvement of microglia and dopamine D1 receptor (D1R) in the frontostriatal circuit due to their known links with mood disorders.

Adolescent mice underwent 8 weeks of PWI before evaluating their depression-like behaviors and the activation status of microglia in the frontostriatal regions. Selective D1-like dopamine receptor agonist SKF-81,297 was administered into the medial prefrontal cortex (mPFC) of PWI mice to assess its antidepressant and anti-microglial activation properties. The effects of SKF-81,297 on inflammatory signaling pathways were examined in BV2 microglial cells. After 8 weeks of PWI, female mice exhibited more severe depression-like behaviors than males, with greater microglial activation in the frontostriatal regions. Microglial activation in mPFC was the most prominent among the three frontostriatal regions examined, and it was positively correlated with the severity of depression-like behaviors. Female PWI mice exhibited increased expression of dopamine D2 receptors (D2R). SKF-81,297 treatment alleviated depression-like behaviors and local microglial activation induced by PWI; however, SKF-81,297 induced these alterations in naïve mice. In vitro, SKF-81,297 decreased pro-inflammatory cytokine release and phosphorylations of JNK and ERK induced by lipopolysaccharide, while in untreated BV2 cells, SKF-81,297 elicited inflammation.

This study highlights a sex-specific susceptibility to PWI-induced neuroinflammation and depression. While targeting the D1R shows potential in alleviating PWI-induced changes, further investigation is required to evaluate potential adverse effects under normal conditions.

Inflammation and metabolic dysfunction impair dopamine neurotransmission, which is thought to serve as a critical mechanism underpinning motivational deficits such as anhedonia across a range of psychiatric and neurological disorders. This difficult-to-treat transdiagnostic symptom has important implications for treatment resistant depression (TRD), and may warrant more targeted therapeutic approaches that address the underlying pathophysiological mechanisms. Using the adrenocorticotrophic hormone (ACTH) model of antidepressant treatment resistance we characterized the relationship between antidepressant-like and anhedonia-like behavioral responses to bupropion, mesocortical tyrosine hydroxylase (TH) expression, chronic low-grade inflammation, and metabolic changes in male rats. We demonstrate that chronic ACTH elicited both an antidepressant resistant- and anhedonia-like phenotype in forced swim and effort-related choice behavioral tasks, respectively. This was associated with decreased TH expression in the brain, increased central and peripheral markers of inflammation, and peripheral metabolic disturbances, including impairment of immune cell insulin action. Multivariate analysis revealed that peripheral interleukin-6 (IL-6) levels, immune cell glucose uptake and disturbance of nucleotide metabolism were strongly associated with anhedonia-like behavior. Post-hoc analyses further confirmed strong correlations between TH expression, inflammation and behavioral performance. These data suggest that stress hormone-induced upregulation of inflammation concurrent with the impairment of insulin-mediated glucose uptake into immune cells is associated with disruption of nucleotide metabolism, and potential impaired central dopamine synthesis contributing to the behavioral expression of anhedonia. These results suggest that immunometabolic perturbations concomitant with impaired insulin action at the level of the immune cell result in a metabolically deficient state that directly impacts nucleotide precursors essential for dopamine synthesis and effortful behavior. These results highlight the potential for immune and metabolic markers for individualized treatment of refractory depression and anhedonia.

The link between gut microbiome and eating behaviours, especially palatable food intake, is a growing focus of scientific investigation. The complex ecosystem of microorganisms in the gut influences host metabolism, immune function and neurobehavioural signalling. This review explores the role of neuroinflammation in dysregulations of food-induced reward signalling and the potential causal role of the gut microbiota on these proinflammatory processes. Particular attention is given to eating disorders (ED, specifically anorexia nervosa, binge eating disorder and bulimia nervosa) and potential links with the gut microbiota, food reward alterations and neuroinflammation. Finally, we propose gut microbiota modulation as a promising therapeutic strategy in food reward alterations and ED.

Inflammatory biomarkers like C-reactive protein (CRP) are elevated in a subset of patients with depression and have been associated with lower functional connectivity (FC) in a ventral striatum (VS) to ventromedial prefrontal cortex (vmPFC) reward circuit and symptoms of anhedonia. Evidence linking these relationships to the effects of inflammation on dopamine is consistent with our recent findings that acute levodopa (L-DOPA) increased VS-vmPFC FC in association with deceased anhedonia in depressed patients with higher but not lower CRP (>2 versus ≤ 2 mg/L). To determine whether repeated L-DOPA administration caused sustained effects on FC and behavior in these patients, medically stable depressed outpatients with CRP > 2 mg/L and anhedonia (n = 18) received one week of three doses of L-DOPA (150-450 mg/day/week with carbidopa) or placebo in a randomized order. Resting-state (rs) and task-based (tb; monetary incentive delay) fMRI, effort-based motivation, and exploratory measures of anhedonia and depression severity were assessed at baseline and after one week of placebo and each dose of L-DOPA. Responses to individual doses of L-DOPA varied across outcomes. For example, VS-vmPFC rs-FC was significantly increased by L-DOPA at 150 and 450 mg/day/week (p < 0.01), whereby approximately half of patients responded optimally to 150 mg/day L-DOPA and approximately half required higher doses for maximum effect. While effort-based motivation was only significantly increased by L-DOPA at 150 mg/day (p < 0.05), it correlated with VS-vmPFC rs-FC at this dose (r = 0.64, p = 0.024), and all L-DOPA doses met a clinically significant threshold of ≥ 10 % increase versus placebo. When comparing the maximum response at any L-DOPA dose to placebo, high effect sizes were observed for these primary outcomes and tb-FC during reward anticipation (dz = 0.82-0.98, p < 0.01), as well as secondary and exploratory measures of anhedonia and depression severity (dz = 0.48-0.97, p < 0.05). Sustained effects on reward circuitry, effort-based motivation, and anhedonia by repeated L-DOPA administration support the therapeutic potential of agents that increase dopamine in depressed patients with higher inflammation.

There is limited information on the role of the Nociceptin/Orphanin FQ receptor (NOPR) in neuroinflammation, and there is growing interest in the participation of the NOPR in depression etiology. This study aims to evaluate the neuroinflammatory effects of the NOPR activation in mice submitted to social defeat protocol (SDP). Firstly, male Swiss mice were submitted to the social defeat protocol during 10 or 20 days and treated with the NOPR agonist Ro 65-6570 (1.5 or 2 mg/kg; ip). Subsequently, behavioral tests were applied to evaluate depressive-like behaviors. Finally, inflammatory cytokines were measured in the animals' brains and blood. A meta-analysis, including 11 experiments, was also conducted to evaluate if the NOPR activation contributes to inflammation. The studies' weights, odds ratios, and confidence intervals were used to calculate the average effect size as the main outcome measure. The software SPSS v.29 and R programming language were used to analyze the data. The SDP and/or NOP agonist reduced distance traveled and exploration rate in the open field test. The SDP and/or the NOP agonist also increased immobility time in the tail suspension test, as well as reduced social interaction. Additionally, the NOP agonist increased the concentration of IL-6 and TNF alpha in the hippocampus, as well as reduced the IL-10 concentration in the hippocampus, but not in prefrontal cortex and serum. The SDP increased the concentration of IL-6 and TNF alpha in animals' serum and prefrontal cortex, but not in the hippocampus. The role of NOPR in neuroinflammation was regardless of the social defeat stress in the hippocampus. Meta-analysis also demonstrated the participation of NOPR activation in inducing inflammation in mice models. We suggest that upregulation of NOPR can activate signaling pathways involved in neuroinflammation, contributing to depression etiology.

Inflammatory stimuli administered to humans and laboratory animals affect mesolimbic and nigrostriatal dopaminergic pathways in association with impaired motivation and motor activity. Alterations in dopaminergic corticostriatal reward and motor circuits have also been observed in depressed patients with increased peripheral inflammatory markers. The effects of peripheral inflammation on dopaminergic pathways and associated neurobiologic mechanisms and consequences have been difficult to measure in patients. Postmortem tissue (n = 11) from an established, translationally-relevant non-human primate model of cytokine-induced depressive behavior involving chronic interferon-alpha (IFN-a) administration was utilized herein to explore the molecular mechanisms of peripheral cytokine effects on striatal dopamine. Dopamine (but not serotonin or norepinephrine) was decreased in the nucleus accumbens (NAcc) and putamen of IFN-a-treated animals (p < 0.05). IFN-a had no effect on number of striatal neurons or dopamine terminal density, suggesting no overt neurodegenerative changes. RNA sequencing examined in the caudate, putamen, substantia nigra, and prefrontal cortical subregions revealed that while IFN-a nominally up-regulated limited numbers of genes enriching inflammatory signaling pathways in all regions, robust, whole genome-significant effects of IFN-a were observed specifically in putamen. Genes upregulated in the putamen primarily enriched synaptic signaling, glutamate receptor signaling, and inflammatory/metabolic pathways downstream of IFN-a, including MAPK and PI3K/AKT cascades. Conversely, gene transcripts reduced by IFN-a enriched oxidative phosphorylation (OXPHOS), protein translation, and pathways regulated by dopamine receptors. Unsupervised clustering identified a gene co-expression module in the putamen that was associated with both IFN-a treatment and low dopamine levels, which enriched similar inflammatory, metabolic, and synaptic signaling pathways. IFN-a-induced reductions in dopamine further correlated with genes related to excitotoxic glutamate, kynurenine, and altered dopamine receptor signaling (r = 0.78-97, p < 0.05). These findings provide insight into the immunologic mechanisms and neurobiological consequences of peripheral inflammation effects on dopamine, which may inform novel treatment strategies targeting inflammatory, metabolic or neurotransmitter systems in depressed patients with high inflammation.

Suicide is defined as the act of a person attempting to take their own life by causing death. Suicide is a complex phenomenon that is influenced by a multitude of factors, including psychosocial, cultural, and religious aspects, as well as genetic, biochemical, and environmental factors. From a biochemical perspective, it is crucial to consider the communication between the endocrine, immune, and nervous systems when studying the etiology of suicide. Several pathologies involve the bidirectional communication between the peripheral activity and the central nervous system by the action of molecules such as cytokines, hormones, and neurotransmitters. These humoral signals, when present in optimal quantities, are responsible for maintaining physiological homeostasis, including mood states. Stress elevates the cortisol and proinflammatory cytokines levels and alter neurotransmitters balance, thereby increasing the risk of developing a psychiatric disorder and subsequently the risk of suicidal behavior. This review provides an integrative perspective about the neurochemical, immunological, and endocrinological disturbances associated with suicidal behavior, with a particular focus on those alterations that may serve as potential risk markers and/or indicators of the state preceding such a tragic act.

Bipolar disorder (BD) is characterized by a complex constellation of emotional, cognitive, and psychomotor disturbances, each deeply intertwined with underlying dysfunctions in large-scale brain networks and neurotransmitter systems. This manuscript integrates recent advances in neuroimaging, neuromodulation, and pharmacological research to provide a comprehensive view of BD's pathophysiology, emphasizing the role of network-specific dysfunctions and their clinical manifestations. We explore how dysregulation within the fronto-limbic network, particularly involving the prefrontal cortex (PFC) and amygdala, underpins the emotional instability that defines both manic and depressive episodes. Additionally, impairments in the central executive network (CEN) and default mode network (DMN) are linked to cognitive deficits, with hyperactivity in the DMN driving rumination and cognitive inflexibility, while CEN underactivity contributes to attentional lapses and impaired executive function. Psychomotor symptoms, which oscillate between hyperactivity in mania and retardation in depression, are closely associated with imbalances in neurotransmitter systems, particularly dopamine and serotonin, within the basal ganglia-thalamo-cortical motor pathway. Recent studies indicate that these psychomotor disturbances are further exacerbated by disruptions in network connectivity, leading to impairments in both motor control and emotional regulation. Emerging therapeutic strategies are discussed, with a focus on neuromodulation techniques such as transcranial magnetic stimulation (TMS) and deep brain stimulation (DBS), which show promise in restoring balance within these critical networks. Furthermore, pharmacological interventions that modulate synaptic functioning and neuronal plasticity offer potential for addressing both the emotional and motor symptoms of BD. This manuscript underscores the need for an integrative treatment approach that simultaneously targets neural circuits and neurotransmitter systems to address the full spectrum of symptoms in BD. Drawing on recent advancements in neurobiological models and therapeutic frameworks, this proposal outlines a pathway for the development of precision-tailored interventions. These approaches are designed to optimize cognitive, emotional, and psychomotor outcomes, ultimately striving to elevate the quality of life for individuals living with bipolar disorder (BD), while remaining firmly grounded in the latest empirical evidence and theoretical insights.

Increased inflammation and associated metabolic disturbances have been shown to affect neurotransmitters and brain circuits, contributing to an immunometabolic phenotype of anhedonic depression. To extend our previous findings on relationships between plasma lipids and antidepressant response to anti-cytokine therapy, we explored in secondary analyses whether lipid-related biomarkers similarly predicted change in anhedonia or functional connectivity (FC) in dopamine-rich corticostriatal reward circuitry in medically-stable, depressed patients with a range of inflammation levels (indexed by plasma C-reactive protein [CRP]) who were administered inflammation-targeted therapies. Relationships were examined between baseline lipids (plasma cholesterols, triglycerides and non-esterified fatty acids) and reduction of anhedonia symptoms in Study 1 (n = 60) after three infusions of infliximab or placebo and change in resting-state FC in Study 2 (n = 31) after acute, within-subject challenge with levodopa (L-DOPA) and placebo. A treatment by inflammation interaction revealed lower anhedonia after infliximab versus placebo (F[1,49] = 5.5, p < 0.05) in patients with, but not without, CRP>3 mg/L (n = 27). A composite score of lipid-related biomarkers (with increasing values reflecting higher concentrations) also precited anhedonia response (post-treatment minus baseline) to infliximab (r = -0.46, p < 0.05) but not placebo (r = 0.14, p = 0.56). Lipid scores similarly predicted CRP-related increases in reward circuit FC after L-DOPA (r = 0.53, p < 0.01) but not placebo (r = 0.20, p = 0.34). Responses to infliximab and L-DOPA were strongest in patients with versus without clinically elevated CRP (>3 mg/L) and/or cholesterol (>150 mg/dL)(p < 0.05). Results highlight a role for dyslipidemia in immunometabolic depression, biomarkers of which, together with CRP, have potential to classify patients indicated for therapies that block inflammation or its effects on neurotransmitters like dopamine.

Inflammatory and metabolic processes are linked to depression, but only 25-30% of depressed patients show low-grade inflammation and metabolic dysregulation associated with atypical, energy-related symptoms (AES). Interventions targeting immuno-metabolic dysregulation could benefit depressed patients, but currently no consensus exists how to best select patients with immuno-metabolic dysregulations. Therefore, we investigated which combinations of circulating C-reactive protein (CRP) and AES could identify those depressed individuals with significant immuno-metabolic dysregulation.

Data are from 1,077 persons with a current Major Depressive Disorder (MDD) of the Netherlands Study of Depression and Anxiety. Immuno-metabolic markers were Interleukin-6 (IL-6), Tumor Necrosis Factor alpha (TNF-α), glycoprotein acetyls, body mass index (BMI), waist circumference, triglycerides, high-density-lipoprotein cholesterol (HDL cholesterol), glucose and leptin. Strata for CRP (≤ 1, < 1 CRP ≤ 3, > 3 mg/L) and AES (score of ≤ 3, 4-5, ≥ 6) were compared on immuno-metabolic markers using analyses of covariance.

Across strata of CRP and AES, there was a dose-response pattern with all higher immuno-metabolic marker levels across higher strata of CRP and AES, with the exception for an association between AES and TNF-α. Persons with both elevated CRP (> 1 mg/L) and high AES (≥ 6) showed a more dysregulated inflammatory and metabolic profile compared to persons with lower CRP and/or AES (p < 0.001).

Our results show a dose-response relationship between both CRP levels and AES with immuno-metabolic risk biomarkers, indicating that CRP and AES combined can capture immuno-metabolic features of MDD. Combining these available and scalable indexes may be an effective strategy to select a patient sample with immuno-metabolic dysregulation who may benefit from treatments targeting inflammatory or metabolic pathways.

Skews in the neutrophil-to-lymphocyte ratio (NLR) and monocyte-to-lymphocyte ratio (MLR) increasingly demonstrate prognostic capability in a range of acute and chronic mental health conditions. There has been a recent uptick in structural and functional magnetic responance imaging data corroborating the role of NLR and MLR in a cluster of neuropsychiatric disorders that are characterized by cognitive, affective, and psychomotor dysfunction. Moreover, these deficits are mostly evident in setting of acute and chronic disease comorbidity implicating aging and immunosenescent processes in the manifestation of these geriatric syndromes. The studies reviewed in this special edition implicate neutrophil and monocyte expansion relative to lymphocytopenia in the sequelae of depression, cognitive and functional decline, as well as provide support from a range of neuroimaging techniques that identify brain alteartions concommitant with expansion of the NLR or MLR and the sequelae of depression, dementia, and functional decline.

Doxorubicin (Dox) is a chemotherapy agent commonly used to treat multiple types of cancers and is associated with cognitive impairment. The goal of this work was to determine the effect of Dox treatment on dopamine release and uptake and behavior in rats. Rats received one dose per week of Dox (2.5 mg/kg, I.V.) and were sacrificed after two or four weeks. Dopamine release and uptake was measured in brain slices with fast-scan cyclic voltammetry (FSCV). A set of rats that received treatment also underwent behavioral testing with the 5-choice serial reaction timed task (5CSRTT) to measure degree of impulsiveness and attention throughout the course of treatment. Dopamine release and uptake increased substantially after treatment with Dox for two weeks compared to controls. After four weeks of treatment, release levels decreased to less than controls while there were no differences in uptake. Treatment of brain slices with pramipexole revealed that dopamine release was equally sensitive to autoregulation after two weeks of Dox treatment, but less sensitive after four weeks. Measurements from the 5CSRTT indicated that, while Dox did not affect attention, it increased impulsiveness after two and three weeks of treatment, but not after four weeks. Treatment with Dox for a short time may elevate dopamine system activity and increase impulsiveness, while longer administration then leads to an underactive dopamine system. To our knowledge this work demonstrates for the first time that Dox can have a biphasic neurochemical and behavioral effect.

Major depressive disorder is a common, disabling mental disorder characterized by extensive etiological and phenotypic heterogeneity. This heterogeneity makes treatment approaches imprecise and often ineffective. Insight into the underlying biological mechanisms underpinning depression and its subtypes may enable more personalized treatments. In this review, we provide an overview of immuno-metabolic depression and illustrate that significant immuno-metabolic dysregulations are present in about 20-30% of people with depression. Such immuno-metabolic depression is characterized by the clustering of 1) atypical, energy-related depressive symptoms such as hypersomnia, fatigue, hyperphagia, and possibly anhedonia, 2) systemic low-grade inflammation with elevated levels of e.g., C-reactive protein, cytokines and glycoprotein acetyls, and 3) metabolic abnormalities involving e.g., obesity, dyslipidaemia, insulin and leptin resistance. Persons with immuno-metabolic depression are at a higher risk for cardiometabolic diseases and seem to respond less well to standard antidepressant treatment. Interventions targeting inflammation, metabolism or lifestyle may be more effective treatment options for individuals with immuno-metabolic depression, in line with principles of precision psychiatry.

While the impact of chronic, low-grade inflammation on cognitive functioning is documented in the context of neurodegenerative disease, less is known about the association between acute increases in inflammation and cognitive functioning in daily life. This study investigated how changes in interleukin-6 (IL-6) levels were associated with performance on an inhibitory control task, the go/no-go task. We further examined whether the opportunity to earn different incentive types (social or monetary) and magnitudes (high or low) was associated with differential performance on the task, depending on IL-6 levels. Using a within-participant design, individuals completed an incentivized go/no-go task before and after receiving the annual influenza vaccine. Multilevel logistic regressions were performed on the trial-level data (Nobs = 30,528). For no-go trials, we did not find significant associations in IL-6 reactivity and changes in trial accuracy between sessions. For go trials, we found significant differences in the associations between IL-6 reactivity and changes in accuracy as a function of the incentive condition. Notably, greater IL-6 reactivity was consistently associated with fewer omission errors (i.e., greater accuracy on go trials) on high-magnitude social incentives (i.e., viewing a picture of a close-other) when compared to both low-magnitude social and high-magnitude monetary incentives. Together, these results suggest that mild fluctuations in inflammation might alter the valuation of an incentive, and possibly a shift toward devoting greater attentional resources when a large social incentive is on the line. Overall, this study sheds light on how everyday, low-grade fluctuations in inflammation may influence cognitive abilities essential for daily life and effective inhibitory control.

Viruses can infiltrate the central nervous system and contribute to depression, which may include alterations in dopamine (DA) metabolism triggered by immune responses though the specific mechanisms involved remain unclear. Here, an electrochemical system to realize the real-time dynamic monitoring of DA with high sensitivity is proposed and it is demonstrated that the viral simulator polyinosinic-polycytidylic acid (poly(I:C)) can inhibit the release of DA (from 5.595 to 0.137 µm) in neurons from the perspective of single cells, cell populations and even in vivo through the combination of multiscale electrodes, including single nanowires, carbon fibers (CFs) and 2D flexible electrodes. These findings are associated with the increase in reactive oxygen species (ROS) produced by microglia. At the molecular level, poly(I:C) significantly decreases the expression of α-synuclein and increases its phosphorylation level, whereas ROS inhibitors can reverse these pathological changes and salvage DA release to half the initial level (≈2.6 µM). These results suggest that viruses may indirectly inhibit DA system function through ROS produced in inflammatory responses and that antioxidant activity may be a potential therapeutic strategy.

Depression and decreased dopamine transporter (DAT) availability are prevalent in Parkinson's disease (PD), yet early predictive biomarkers are lacking. This study investigates the longitudinal associations between cerebrospinal fluid (CSF) neuroglial activation markers, sTREM2 and YKL-40, and depression, as well as DAT availability, in PD patients.

We analyzed data from 172 PD subjects and 80 matched healthy controls from a large longitudinal study. A generalized linear mixed-effects model assessed the longitudinal associations of CSF sTREM2 and YKL-40 with depression and DAT availability. Causal mediation analysis determined if DAT decline mediated the effects of sTREM2 and YKL-40 on depression.

Cross-sectional analysis revealed a negative correlation between CSF sTREM2 and baseline depression scores in PD patients. CSF YKL-40 negatively correlated with baseline left caudate nucleus, left anterior putamen, and right anterior putamen specific binding ratios (SBR). Longitudinally, higher baseline CSF sTREM2 predicted faster depression progression (β = 0.828, p < 0.001) and a rapid decline in right putamen SBR (β = 0.072, p = 0.016). Similarly, higher baseline CSF YKL-40 predicted faster depression progression (β = 0.586, p = 0.004) and a decline in left anterior putamen SBR (β = 0.058, p = 0.035). Causal mediation analysis indicated that baseline CSF sTREM2 accelerated depression progression via its effect on right putamen and right anterior putamen SBR (Indirect effect = 0.103, p = 0.020; Indirect effect = 0.129, p = 0.016).

CSF sTREM2 and YKL-40 are effective predictors for depression and DAT decline in PD, suggesting that neuroglial activation-induced dopaminergic neuron apoptosis significantly contributes to depression onset in PD.

The novel serum C-reactive protein-triglyceride glucose index (CTI) has been identified as an ideal parameter that integrates inflammation and insulin resistance, which are potential mechanisms underlying depressive symptoms. Our research aimed to investigate the association between CTI and depressive symptoms.

Our cross-sectional investigation utilized data from the National Health and Nutrition Examination Survey conducted between 2005 and 2010. The integrated CTI was calculated as 0.412 × Ln (C-reactive protein) (mg/dL) + Ln [triglyceride (mg/dL) × fasting glucose (mg/dL)/2]. The severity of depressive symptoms was evaluated through the continuous Patient Health Questionnaire-9 (PHQ-9) scores, and the categorical definition of depressive symptoms (PHQ-9 score ≥ 10) reflected moderate to severe symptoms. Survey-weighted linear and logistic regression models were conducted to establish the correlation between CTI and PHQ-9 scores, and between CTI and depressive symptoms. Moreover, subgroup analyses, interaction tests, and smoothed curve fitting were performed to scrutinize the steadiness of the results.

A total of 5,954 participants were enrolled in our study, including 477 with depressive symptoms and 5,477 without. The results revealed a significant positive relationship between CTI and PHQ-9 scores (β: 0.40, 95% CI: 0.25,0.55, p < 0.001) and depressive symptoms (OR: 1.30, 95% CI: 1.06,1.61, p = 0.02). Additionally, individuals in the fourth quartile of CTI exhibited a higher likelihood of depressive symptoms than those in the first quartile (PHQ-9 score: β: 0.83, 95% CI: 0.39,1.26, p < 0.001; depressive symptoms: OR: 2.00, 95% CI:1.19,3.36, p = 0.01). Smooth curve fitting and subgroup analyses consistently demonstrated the positive relationship.

Elevated CTI was correlated with a higher risk of depressive symptoms, underscoring CTI as a potential clinical indicator for identifying and stratifying depressive symptoms.

Not applicable.

The dopaminergic system is a complex and powerful neurotransmitter system in the brain. It plays an important regulatory role in motivation, reward, cognition, and motor control. In recent decades, research in the field of the dopaminergic system and neurons has increased exponentially and is gradually becoming a point of intervention in the study and understanding of a wide range of neurological diseases related to human health. Studies have shown that the dopaminergic system and neurons are involved in the development of many neurological diseases (including, but not limited to Parkinson's disease, schizophrenia, depression, attention deficit hyperactivity disorder, etc.) and that dopaminergic neurons either have too much stress or too weak function in the dopaminergic system can lead to disease. Therefore, targeting dopaminergic neurons is considered key to treating these diseases. This article provides a comprehensive review of the dopaminergic system and neurons in terms of brain region distribution, physiological function and subtypes of dopaminergic neurons, as well as the role of the dopaminergic system and neurons in a variety of diseases.

Natural variation in ovarian steroid hormones across the female lifespan contributes to an increased risk for depressive and posttraumatic stress disorder (PTSD) symptoms in women. However, minimal work has focused on understanding the impacts of reproductive aging on the brain and behavioral health of trauma-exposed women. This systematic review examines the bidirectional relationship between trauma-related psychopathology and reproductive aging.

Following PRISMA guidelines, a systematic review of PubMed, PsychInfo, and Medline databases was undertaken to identify controlled studies on how trauma history impacts psychopathology and menopause symptoms during reproductive aging.

Twenty-one studies met the eligibility criteria, with only four utilizing the gold standard STRAW+ 10 criteria for defining reproductive aging stages. The peri and postmenopausal periods appear to be particularly vulnerable phases for individuals with trauma exposure. Menopause symptoms and trauma-related psychopathology symptom severity increase during reproductive aging with increases in the degree of trauma exposure. However, mechanistic insights that may explain this interaction are currently neglected in this area of research.

There is a significant lack of understanding regarding how reproductive aging and its related neuroendocrine changes impact the brain to influence PTSD and depression symptoms related to trauma exposure. This lack of basic understanding impedes the ability to identify, assess, and treat PTSD and depressive symptoms in trauma-exposed women most effectively, and mitigate the long-term consequences of these behavioral health symptoms on morbidity and mortality in aging women.

ADHD symptoms are associated with emotional problems such as depressive and anxiety symptoms from early childhood to adulthood, with the association increasing with age. A shared aetiology and/or a causal relationship could explain their correlation. In the current study, we explore these explanations for the association between ADHD symptoms and emotional problems from childhood to adulthood.

Data were drawn from the Twins Early Development Study (TEDS), including 3675 identical and 7063 non-identical twin pairs. ADHD symptoms and emotional symptoms were reported by parents from childhood to adulthood. Self-report scales were included from early adolescence. Five direction of causation (DoC) twin models were fitted to distinguish whether associations were better explained by shared aetiology and/or causal relationships in early childhood, mid-childhood, early adolescence, late adolescence, and early adulthood. Follow-up analyses explored associations for the two subdomains of ADHD symptoms, hyperactivity-impulsivity and inattention, separately.

The association between ADHD symptoms and emotional problems increased in magnitude from early childhood to adulthood. In the best-fitting models, positive genetic overlap played an important role in this association at all stages. A negative causal effect running from ADHD symptoms to emotional problems was also detected in early childhood and mid-childhood. When distinguishing ADHD subdomains, the apparent protective effect of ADHD symptoms on emotional problems in childhood was mostly driven by hyperactivity-impulsivity.

Genetic overlap plays an important role in the association between ADHD symptoms and emotional problems. Hyperactivity-impulsivity may protect children from emotional problems in childhood, but this protective effect diminishes after adolescence.

Takayasu arteritis (TA) is associated with an increased risk of developing complicated comorbidities, which can bring both psychological and physical burdens to the patients.

TA is found to carry a high risk of developing depression. This research aimed to investigate the risk factors and prognosis of depression in TA patients.

A longitudinal observation cohort was conducted on TA patients with or without depression to explore the clinical characteristics.

In this cohort study, 90 TA patients were split into two groups with or without depression. Depression was evaluated by the Hospital Anxiety and Depression Scale (HADS) in TA patients. TA patients with depression were followed up for at least 3 months. We used multivariate logistic regression analysis to find the risk factors and Kaplan-Meier curve analysis to determine the prognosis.

We concluded 90 TA patients in this research, 29 of whom were in depression. Indian Takayasu's Arteritis Activity Score (ITAS2010) ⩾2 (odds ratio (OR) (95% confidence interval, CI) 26.664 (2.004-354.741), p = 0.013), interleukin-6 (IL-6) (OR (95% CI) 1.070 (1.022-1.121), p = 0.004), prednisone equivalents (OR (95% CI) 1.101 (1.030-1.177), p = 0.005), and carotidynia (OR (95% CI) 5.829 (1.142-29.751), p = 0.034) have been shown independent risk factors for depression in TA patients. We also identified the association between disease remission with the improvement of HADS-D score (Log-rank p = 0.005, hazard ratio (HR) 0.25) and depression (Log-rank p = 0.043, HR 0.28).

Aggressive treatment to achieve remission can promote improvement of depression in patients with TA. Screening for depression should also be performed in patients with elevated disease activity, IL-6, glucocorticoid use, and carotidynia.

Due to the heterogeneous nature of depression, the underlying etiological mechanisms greatly differ among individuals, and there are no known subtype-specific biomarkers to serve as precise targets for therapeutic efficacy. The extensive research efforts over the past decades have not yielded much success, and the currently used first-line conventional antidepressants are still ineffective for close to 66% of patients. Most clinicians use trial-and-error treatment approaches, which seem beneficial to only a fraction of patients, with some eventually developing treatment resistance. Here, we review evidence from both preclinical and clinical studies on the pathogenesis of depression and antidepressant treatment response. We also discuss the efficacy of the currently used pharmacological and non-pharmacological approaches, as well as the novel emerging therapies. The review reveals that the underlying mechanisms in the pathogenesis of depression and antidepressant response, are not specific, but rather involve an interplay between various neurotransmitter systems, inflammatory mediators, stress, HPA axis dysregulation, genetics, and other psycho-neurophysiological factors. None of the current depression hypotheses sufficiently accounts for the interactional mechanisms involved in both its etiology and treatment response, which could partly explain the limited success in discovering efficacious antidepressant treatment. Effective management of treatment-resistant depression (TRD) requires targeting several interactional mechanisms, using subtype-specific and/or personalized therapeutic modalities, which could, for example, include multi-target pharmacotherapies in augmentation with psychotherapy and/or other non-pharmacological approaches. Future research guided by interaction mechanisms hypotheses could provide more insights into potential etiologies of TRD, precision biomarker targets, and efficacious therapeutic modalities.

Autoimmune hepatitis(AIH) is a chronic progressive inflammatory liver disease induced by loss of immune tolerance. The role of circulating metabolites in disease pathogenesis is unclear. This study aimed to investigate potential causal links between plasma metabolites and AIH risk by employing a two-sample Mendelian randomization approach. A comprehensive bidirectional two-sample Mendelian randomization analysis was conducted using genome-wide significant variant-metabolite and variant-AIH associations in European ancestry individuals. Various methods assessed causal relationships among 1400 metabolites and AIH, incorporating sensitivity analyses to evaluate pleiotropy and heterogeneity. Fifty-eight metabolites displayed possible associations, including increased AIH risk with genetically predicted higher kynurenine (p = 2.79 × 10- 5, OR: 1.64, 95% CI 1.30-2.07) and a protective effect for the dopamine sulfate ratio (p = 1.06 × 10- 5,OR: 0.62, 95% CI 0.49-0.79). Reciprocal analysis revealed a causal effect of AIH on kynurenine( p = 2.79 × 10- 5, OR: 1.64, 95% CI 1.30-2.07), but not on the dopamine sulfate ratio(p = 0.691, OR: 1.05, 95% CI 0.67-1.64). Our genetics-based approach provides evidence supporting a causal role for specific metabolite levels in AIH risk. The results deliver evidence supporting a causal effect of a specific metabolite ratio(dopamine 4-sulfate/dopamine 3-O-sulfate) on AIH risk. Experimental validation and mechanistic examinations are warranted to confirm findings.