Dopamine D1 receptor in medial prefrontal cortex mediates the effects of TAAR1 activation on chronic stress-induced cognitive and social deficits.

Trace amine-associated receptor 1 (TAAR1) is an intracellular expressed G-protein-coupled receptor that is widely expressed in major dopaminergic areas and plays a crucial role in modulation of central dopaminergic neurotransmission and function. Pharmacological studies have clarified the roles of dopamine D1 receptor (D1R) in the medial prefrontal cortex (mPFC) in cognitive function and social behaviors, and chronic stress can inhibit D1R expression due to its susceptibility. Recently, we identified TAAR1 in the mPFC as a potential target for treating chronic stress-induced cognitive and social dysfunction, but whether D1R is involved in mediating the effects of TAAR1 agonist remains unclear. Combined genomics and transcriptomic studies revealed downregulation of D1R in the mPFC of TAAR1-/- mice. Molecular dynamics simulation showed that hydrogen bond, salt bridge, and Pi-Pi stacking interactions were formed between TAAR1 and D1R indicating a stable TAAR1-D1R complex structure. Using pharmacological interventions, we found that D1R antagonist disrupted therapeutic effect of TAAR1 partial agonist RO5263397 on stress-related cognitive and social dysfunction. Knockout TAAR1 in D1-type dopamine receptor-expressing neurons reproduced adverse effects of chronic stress, and TAAR1 conditional knockout in the mPFC led to similar deficits, along with downregulation of D1R expression, all of these effects were ameliorated by viral overexpression of D1R in the mPFC, suggesting the functional interaction between TAAR1 and D1R. Collectively, our data elucidate the possible molecular mechanism that D1R in the mPFC mediates the effects of TAAR1 activation on chronic stress-induced cognitive and social deficits.

[Research progress of trace amine-associated receptor 1 signaling pathways].

Trace amine-associated receptor 1 (TAAR1) is a classical type of G-protein-coupled receptor, which is widely distributed in the brain of mammals, especially in the limbic system and the region rich in monoaminergic neurons, and it is a highly conserved TAAR subtype in all species. TAAR1 can specifically respond to endogenous trace amines in the central nervous system and peripheral tissues, and plays an important role in the pathophysiological mechanisms involving the dysregulation of monoamine system and glutamate system leading to mental disorders. In addition, TAAR1 modulator can act on inwardly rectifying potassium channels and regulate synaptic transmission and neuronal activity. According to the latest research findings, TAAR1 exerts a series of functions by regulating signal pathways and substrate phosphorylation, which is related to emotion, cognition, fear and addiction. Therefore, we conducted a detailed review of relevant studies on the TAAR1 signaling pathways, aiming at revealing the great potential of TAAR1 as a new target for drug treatment of neuropsychiatric disorders.

A distinctive subcortical functional connectivity pattern linking negative affect and treatment outcome in major depressive disorder.

Major depressive disorder (MDD) is associated with functional disturbances in subcortical regions. In this naturalistic prospective study (NCT03294525), we aimed to investigate relationships among subcortical functional connectivity (FC), mood symptom profiles and treatment outcome in MDD using multivariate methods. Medication-free participants with MDD (n = 135) underwent a functional magnetic resonance imaging scan at baseline and completed posttreatment clinical assessment after 8 weeks of antidepressant monotherapy. We used partial least squares (PLS) correlation analysis to explore the association between subcortical FC and mood symptom profiles. FC score, reflecting the weighted representation of each individual in this association, was computed. Replication analysis was undertaken in an independent sample (n = 74). We also investigated the relationship between FC score and treatment outcome in the main sample. A distinctive subcortical connectivity pattern was found to be associated with negative affect. In general, higher FC between the caudate, putamen and thalamus was associated with greater negative affect. This association was partly replicated in the independent sample (similarity between the two samples: r = 0.66 for subcortical connectivity, r = 0.75 for mood symptom profile). Lower FC score predicted both remission and response to treatment after 8 weeks of antidepressant monotherapy. The emphasis here on the role of dorsal striatum and thalamus consolidates prior work of subcortical connectivity in MDD. The findings provide insight into the pathogenesis of MDD, linking subcortical FC with negative affect. However, while the FC score significantly predicted treatment outcome, the low odds ratio suggests that finding predictive biomarkers for depression remains an aspiration.

Dorsal CA3 overactivation mediates witnessing stress-induced recognition memory deficits in adolescent male mice.

Witnessing violent or traumatic events is common during childhood and adolescence and could cause detrimental effects such as increased risks of psychiatric disorders. This stressor could be modeled in adolescent laboratory animals using the chronic witnessing social defeat (CWSD) paradigm, but the behavioral consequences of CWSD in adolescent animals remain to be validated for cognitive, anxiety-like, and depression-like behaviors and, more importantly, the underlying neural mechanisms remain to be uncovered. In this study, we first established the CWSD model in adolescent male mice and found that CWSD impaired cognitive function and increased anxiety levels and that these behavioral deficits persisted into adulthood. Based on the dorsal-ventral functional division in hippocampus, we employed immediate early gene c-fos immunostaining after behavioral tasks and found that CWSD-induced cognition deficits were associated with dorsal CA3 overactivation and anxiety-like behaviors were associated with ventral CA3 activity reduction. Indeed, chemogenetic activation and inhibition of dorsal CA3 neurons mimicked and reversed CWSD-induced recognition memory deficits (not anxiety-like behaviors), respectively, whereas both inhibition and activation of ventral CA3 neurons increased anxiety-like behaviors in adolescent mice. Finally, chronic administration of vortioxetine (a novel multimodal antidepressant) successfully restored the overactivation of dorsal CA3 neurons and the cognitive deficits in CWSD mice. Together, our findings suggest that dorsal CA3 overactivation mediates CWSD-induced recognition memory deficits in adolescent male mice, shedding light on the pathophysiology of adolescent CWSD-induced adverse effects and providing preclinical evidence for early treatment of stress-induced cognitive deficits.

TAAR1 in dentate gyrus is involved in chronic stress-induced impairments in hippocampal plasticity and cognitive function.

Multiple lines of evidence suggest that the trace amine-associated receptor 1 (TAAR1) holds promise as a potential target for stress-related disorders, such as treating major depressive disorder (MDD). The role of TAAR1 in the regulation of adult neurogenesis is recently supported by transcriptomic data. However, it remains unknown whether TAAR1 in dentate gyrus (DG) mediate chronic stress-induced negative effects on hippocampal plasticity and related behavior in mice. The present study consisted of a series of experiments using RNAscope, genetic approaches, behavioral tests, immunohistochemical staining, Golgi-Cox technique to unravel the effects of TAAR1 on alterations of dentate neuronal plasticity and cognitive function in the chronic social defeat stress model. The mice subjected to chronic defeat stress exhibited a noteworthy decrease in the mRNA level of TAAR1 in DG. Additionally, they exhibited compromised social memory and spatial object recognition memory, as well as impaired proliferation and maturation of adult-born dentate granule cells. Moreover, the selective knockout TAAR1 in DG mostly mimicked the cognitive function deficits and neurogenesis impairment induced by chronic stress. Importantly, the administration of the selective TAAR1 partial agonist RO5263397 during stress exposure attenuated the adverse effects of chronic stress on cognitive function, adult neurogenesis, dendritic arborization, and the synapse number of dentate neurons in DG. In summary, our findings suggest that TAAR1 plays a crucial role in mediating the detrimental effects of chronic stress on hippocampal plasticity and cognition. TAAR1 agonists exhibit therapeutic potential for individuals suffering from cognitive impairments associated with MDD.

Fluoxetine reverses early-life stress-induced depressive-like behaviors and region-specific alterations of monoamine transporters in female mice.

The sex difference that females are more vulnerable to depression than males has been recently replicated in an animal model of early-life stress (ES) called the limited bedding and nesting material (LBN) paradigm. Adopting this animal model, we have previously examined the effects of ES on monoamine transporter (MATs) expression in stress-related regions in adult female mice, and the reversal effects of a novel multimodal antidepressant, vortioxetine. In this study, replacing vortioxetine with a classical antidepressant, fluoxetine, we aimed to replicate the ES effects in adult female mice and to elucidate the commonality and differences between fluoxetine and vortioxetine. We found that systemic 30-day treatment with fluoxetine successfully reversed ES-induced depression-like behaviors (especially sucrose preference) in adult female mice. At the molecular level, we largely replicated the ES effects, such as reduced serotonin transporter (SERT) expression in the amygdala and increased norepinephrine transporter (NET) expression in the medial prefrontal cortex (mPFC) and hippocampus. Similar reversal effects of fluoxetine and vortioxetine were observed, including SERT in the amygdala and NET in the mPFC, whereas different reversal effects were observed for NET in the hippocampus and vesicular monoamine transporters expression in the nucleus accumbens. Overall, these results demonstrate the validity of the LBN paradigm to induce depression-like behaviors in female mice, highlight the involvement of region-specific MATs in ES-induced depression-like behaviors, and provide insights for further investigation of neurobiological mechanisms, treatment, and prevention associated with depression in women.

Advances in functional MRI research in bipolar disorder: from the perspective of mood states.

Bipolar disorder is characterised by recurrent and alternating episodes of mania/hypomania and depression. Current breakthroughs in functional MRI techniques have uncovered the functional neuroanatomy of bipolar disorder. However, the pathophysiology underlying mood instability, mood switching and the development of extreme mood states is less well understood. This review presents a comprehensive overview of current evidence from functional MRI studies from the perspective of mood states. We first summarise the disrupted brain activation patterns and functional connectivity that have been reported in bipolar disorder, irrespective of the mood state. We next focus on research that solely included patients in a single mood state for a better understanding of the pathophysiology of bipolar disorder and research comparing patients with different mood states to dissect mood state-related effects. Finally, we briefly summarise current theoretical models and conclude this review by proposing potential avenues for future research. A comprehensive understanding of the pathophysiology with consideration of mood states could not only deepen our understanding of how acute mood episodes develop at a neurophysiological level but could also facilitate the identification of biological targets for personalised treatment and the development of new interventions for bipolar disorder.

Brain functional changes across mood states in bipolar disorder: from a large-scale network perspective.

BACKGROUND: Exploring the neural basis related to different mood states is a critical issue for understanding the pathophysiology underlying mood switching in bipolar disorder (BD), but research has been scarce and inconsistent. METHODS: Resting-state functional magnetic resonance imaging data were acquired from 162 patients with BD: 33 (hypo)manic, 64 euthymic, and 65 depressive, and 80 healthy controls (HCs). The differences of large-scale brain network functional connectivity (FC) between the four groups were compared and correlated with clinical characteristics. To validate the generalizability of our findings, we recruited a small longitudinal independent sample of BD patients (n = 11). In addition, we examined topological nodal properties across four groups as exploratory analysis. RESULTS: A specific strengthened pattern of network FC, predominantly involving the default mode network (DMN), was observed in (hypo)manic patients when compared with HCs and bipolar patients in other mood states. Longitudinal observation revealed an increase in several network FCs in patients during (hypo)manic episode. Both samples evidenced an increase in the FC between the DMN and ventral attention network, and between the DMN and limbic network (LN) related to (hypo)mania. The altered network connections were correlated with mania severity and positive affect. Bipolar depressive patients exhibited decreased FC within the LN compared with HCs. The exploratory analysis also revealed an increase in degree in (hypo)manic patients. CONCLUSIONS: Our findings identify a distributed pattern of large-scale network disturbances in the unique context of (hypo)mania and thus provide new evidence for our understanding of the neural mechanism of BD.

Proinflammatory phenotype in major depressive disorder with adulthood adversity: In line with social signal transduction theory of depression.

BACKGROUND: The social signal transduction theory of depression proposes that life stress can be transformed into inflammatory signals, and ultimately lead to the development of major depressive disorder (MDD). The hypotheses of this study were: (1) The pro-inflammatory effect of life stress was only seen in patients with MDD, but not in healthy controls (HCs); (2) Inflammation can mediate the relationship between life stress and depressive symptoms. METHODS: This study included 170 MDD patients and 196 HCs, and 13 immune-inflammatory biomarkers closely related to MDD were measured, principal component analysis (PCA) was adopted to extract the inflammatory index. Life stress was assessed by Life Event Scale (LES), a total score of >32 points on the LES was considered as adulthood adversity (AA). Path analyses were used to explore the relationship among adulthood stress, inflammatory index, and severity of depression. RESULTS: Among MDD patients, α2M, CXCL-1, IL-1ß, and TLR-1 levels were higher in patients with AA than non-AA group (all FDR-adjusted P values <0.05), meanwhile, the levels of CCL-2 and IL-18 were lower. Path analyses suggested that pro- and anti-inflammatory index could mediate the association between AA and severity of depression in MDD patients. CONCLUSION: This study found that inflammatory signals can mediate the relationship between adulthood adversity and depression, however, the causal relationship need to be further confirmed. These findings shed light on further understanding the theory of social signal transduction in MDD and provide clues for stress management and controlling inflammation strategies in depression. CLINICAL TRIALS: NCT02023567.

Major depressive disorder with suicidal ideation or behavior in Chinese population: A scoping review of current evidence on disease assessment, burden, treatment and risk factors.

BACKGROUND: Identifying and managing major depressive disorder (MDD) patients with suicidal ideation or behavior (MDSI) is critical for reducing the disease burden. This scoping review aims to map the existing evidence related to MDSI in the Chinese population. METHOD: A scoping review was conducted to summarize the published evidence regarding epidemiology or disease burden, evaluation, diagnosis, management, and prognosis of MDSI. The search strategy imposed restriction on English or Chinese publications between 1 January 2011 and 28 February 2022. RESULTS: Of the 14,005 identified records, 133 met the eligibility criteria and were included for analysis. The included studies were characterized as high heterogeneity in evaluation of suicidal ideation or behavior. Compared with MDD patients without suicidal ideation or behavior, MDSI patients were more likely to suffer from psychological and somatic symptoms, social function impairment, and lower quality of life. Younger age, female gender, longer disease course, and comorbid psychological or physical symptoms were consistently found to be risk factors of suicidal ideation or behavior. Relevant research gaps remain regarding comprehensive evaluation of standard clinical diagnosis, disease burden, social-cultural risk factors, and effectiveness of interventions targeting MDSI. Studies with large sample size, representative population are warranted to provide high-quality evidence. CONCLUSIONS: MDD patients with suicidal ideation or behavior should be prioritized in treatment and resource allocation. Heterogeneity exists in the definition and evaluation of MDSI in different studies. To better inform clinical practice, it is imperative to establish a unified standard for evaluation and diagnosis of suicidal ideation or behavior among MDD population.

Intrinsic functional connectivity correlates of cognitive deficits involving sustained attention and executive function in bipolar disorder.

BACKGROUND: The neural correlate of cognitive deficits in bipolar disorder (BD) is an issue that warrants further investigation. However, relatively few studies have examined the intrinsic functional connectivity (FC) underlying cognitive deficits involving sustained attention and executive function at both the region and network levels, as well as the different relationships between connectivity patterns and cognitive performance, in BD patients and healthy controls (HCs). METHODS: Patients with BD (n = 59) and HCs (n = 52) underwent structural and resting-state functional magnetic resonance imaging and completed the Wisconsin Card Sorting Test (WCST), the continuous performance test and a clinical assessment. A seed-based approach was used to evaluate the intrinsic FC alterations in three core neurocognitive networks (the default mode network [DMN], the central executive network [CEN] and the salience network [SN]). Finally, we examined the relationship between FC and cognitive performance by using linear regression analyses. RESULTS: Decreased FC was observed within the DMN, in the DMN-SN and DMN-CEN and increased FC was observed in the SN-CEN in BD. The alteration direction of regional FC was consistent with that of FC at the brain network level. Decreased FC between the left posterior cingulate cortex and right anterior cingulate cortex was associated with longer WCST completion time in BD patients (but not in HCs). CONCLUSIONS: These findings emphasize the dominant role of the DMN in the psychopathology of BD and provide evidence that cognitive deficits in BD may be associated with aberrant FC between the anterior and posterior DMN.

The causal involvement of the BDNF-TrkB pathway in dentate gyrus in early-life stress-induced cognitive deficits in male mice.

Cognitive dysfunction is a significant, untreated clinical need in patients with psychiatric disorders, for which preclinical studies are needed to understand the underlying mechanisms and to identify potential therapeutic targets. Early-life stress (ELS) leads to long-lasting deficits of hippocampus-dependent learning and memory in adult mice, which may be associated with the hypofunction of the brain-derived neurotrophic factor (BDNF) and its high-affinity receptor, tropomyosin receptor kinase B (TrkB). In this study, we carried out eight experiments using male mice to examine the causal involvement of the BDNF-TrkB pathway in dentate gyrus (DG) and the therapeutic effects of the TrkB agonist (7,8-DHF) in ELS-induced cognitive deficits. Adopting the limited nesting and bedding material paradigm, we first demonstrated that ELS impaired spatial memory, suppressed BDNF expression and neurogenesis in the DG in adult mice. Downregulating BDNF expression (conditional BDNF knockdown) or inhibition of the TrkB receptor (using its antagonist ANA-12) in the DG mimicked the cognitive deficits of ELS. Acute upregulation of BDNF (exogenous human recombinant BDNF microinjection) levels or activation of TrkB receptor (using its agonist, 7,8-DHF) in the DG restored ELS-induced spatial memory loss. Finally, acute and subchronic systemic administration of 7,8-DHF successfully restored spatial memory loss in stressed mice. Subchronic 7,8-DHF treatment also reversed ELS-induced neurogenesis reduction. Our findings highlight BDNF-TrkB system as the molecular target of ELS-induced spatial memory deficits and provide translational evidence for the intervention at this system in the treatment of cognitive deficits in stress-related psychiatric disorders, such as major depressive disorder.

[Research progress on the immunomodulatory effects and mechanisms of trace amine-associated receptor 1].

Trace amines are endogenous molecules distributed in the central nervous system and peripheral tissues that resemble common biogenic amines in terms of subcellular localization, chemical structure, and metabolism. Trace amine-associated receptor (TAAR) is a kind of evolutionarily conserved G-protein-coupled receptors in vertebrates, in which TAAR1 is a functional regulator of monoamine transmitters such as dopamine and serotonin. TAAR1 is widely considered as a potential therapeutic target for schizophrenia, depression and drug addiction. Moreover, TAAR1 is also expressed in peripheral tissues. The homeostasis imbalance of trace aminergic system can induce over-activation of peripheral immune system and central immune inflammatory response. TAAR1 modulators are becoming potential emerging drugs for the treatment of immune-related illnesses, because they may play a major role in the activation or modulation of immune response.

Aberrant modular segregation of brain networks in female patients with bulimia nervosa.

OBJECTIVE: Bulimia nervosa (BN) is an eating disorder associated with the dysfunction of intrinsic brain networks. However, whether the network disruptions in BN patients manifest as dysconnectivity or imbalances of network modular segregation remains unclear. METHOD: We collected data from 41 women with BN and 41 matched healthy control (HC) women. We performed graph theory analysis based on resting-state functional magnetic resonance imaging (RS-fMRI) data; then, we computed the participation coefficient (PC) among brain modules to characterize the modular segregation for the BN and HC groups. The number of intra- and inter-modular connections was calculated to explain the PC changes. Additionally, we examined the potential associations of the measures mentioned above with clinical variables within the BN group. RESULTS: Compared with the HC group, the BN group showed significantly decreased PC in the fronto-parietal network (FPN), cingulo-opercular network (CON), and cerebellum (Cere). Additionally, the number of intra-modular connections of the default mode network (DMN) and the number of the inter-modular connections between the DMN and CON, FPN and Cere, and CON and Cere in the BN group were lower than those in the HC group. The nodal level analysis showed that the BN group had a decreased PC of the anterior prefrontal cortex (aPFC), dorsal frontal cortex (dFC), inferior parietal lobule (IPL), thalamus, and angular gyrus. Further, these metrics were significantly correlated with clinical variables in the BN group. DISCUSSION: These findings may provide novel insights to capture atypical topologies associated with pathophysiology mechanisms and clinical symptoms underlying BN.

Eight-week antidepressant treatment changes intrinsic functional brain topology in first-episode drug-naïve patients with major depressive disorder.

BACKGROUND: A recent study revealed disrupted topological organization of whole-brain networks in patients with major depressive disorder (MDD); however, these results were mostly driven by recurrent MDD patients, rather than first-episode drug-naïve (FEDN) patients. Furthermore, few longitudinal studies have explored the effects of antidepressant therapy on the topological organization of whole-brain networks. METHODS: We collected clinical and neuroimaging data from 159 FEDN MDD patients and 152 normal controls (NCs). A total of 115 MDD patients completed an eight-week antidepressant treatment procedure. Topological features of brain networks were calculated using graph theory-based methods and compared between FEDN MDD patients and NCs, as well as before and after treatment. RESULTS: Decreased global efficiency, local efficiency, small-worldness, and modularity were found in pretreatment FEDN MDD patients compared with NCs. Nodal degrees, betweenness, and efficiency decreased in several networks compared with NCs. After antidepressant treatment, the global efficiency increased, while the local efficiency, the clustering coefficient of the network, the path length, and the normalized characteristic path length decreased. Moreover, the reduction rate of the normalized characteristic path length was positively correlated with the reduction rate of retardation factor scores. LIMITATIONS: The interaction effects of groups and time on the topological features were not explored because of absence of the eighth-week data of NC group. CONCLUSIONS: The topological architecture of functional brain networks is disrupted in FEDN MDD patients. After antidepressant therapy, the global efficiency shifted toward recovery, but the local efficiency deteriorated, suggesting a correlation between recovery of retardation symptoms and global efficiency.

The Nucleus Accumbens CRH-CRHR1 System Mediates Early-Life Stress-Induced Sleep Disturbance and Dendritic Atrophy in the Adult Mouse.

Adverse experiences in early life have long-lasting negative impacts on behavior and the brain in adulthood, one of which is sleep disturbance. As the corticotropin-releasing hormone (CRH)-corticotropin-releasing hormone receptor 1 (CRHR1) system and nucleus accumbens (NAc) play important roles in both stress responses and sleep-wake regulation, in this study we investigated whether the NAc CRH-CRHR1 system mediates early-life stress-induced abnormalities in sleep-wake behavior in adult mice. Using the limited nesting and bedding material paradigm from postnatal days 2 to 9, we found that early-life stress disrupted sleep-wake behaviors during adulthood, including increased wakefulness and decreased non-rapid eye movement (NREM) sleep time during the dark period and increased rapid eye movement (REM) sleep time during the light period. The stress-induced sleep disturbances were accompanied by dendritic atrophy in the NAc and both were largely reversed by daily systemic administration of the CRHR1 antagonist antalarmin during stress exposure. Importantly, Crh overexpression in the NAc reproduced the effects of early-life stress on sleep-wake behavior and NAc morphology, whereas NAc Crhr1 knockdown reversed these effects (including increased wakefulness and reduced NREM sleep in the dark period and NAc dendritic atrophy). Together, our findings demonstrate the negative influence of early-life stress on sleep architecture and the structural plasticity of the NAc, and highlight the critical role of the NAc CRH-CRHR1 system in modulating these negative outcomes evoked by early-life stress.

TNF-α, IL-6 and hsCRP in patients with melancholic, atypical and anxious depression: an antibody array analysis related to somatic symptoms.

Background: The association between inflammation and major depressive disorder (MDD) remains poorly understood, given the heterogeneity of patients with MDD. Aims: We investigated inflammatory markers, such as interleukin (IL)-6, high-sensitivity C reactive protein (hsCRP) and tumour necrosis factor-α (TNF-α) in melancholic, atypical and anxious depression and explored whether baseline inflammatory protein levels could indicate prognosis. Methods: The sample consisted of participants (aged 18-55 years) from a previously reported multicentre randomised controlled trial with a parallel-group design registered with ClinicalTrials.gov, including melancholic (n=44), atypical (n=37) and anxious (n=44) patients with depression and healthy controls (HCs) (n=33). Subtypes of MDD were classified according to the 30-item Inventory of Depressive Symptomatology, Self-Rated Version and the 17-item Hamilton Depression Rating Scale. Blood levels of TNF-α, IL-6 and hsCRP were assessed using antibody array analysis. Results: Patients with MDD, classified according to melancholic, atypical and anxious depression subtypes, and HCs did not differ significantly in baseline TNF-α, IL-6 and hsCRP levels after adjustment. In patients with anxious depression, hsCRP levels increased significantly if they experienced no pain (adjusted (adj.) p=0.010) or mild to moderate pain (adj. p=0.038) compared with those with severe pain. However, the patients with anxious depression and severe pain showed a lower trend in hsCRP levels than patients with atypical depression who experienced severe pain (p=0.022; adj. p=0.155). Baseline TNF-α (adj. p=0.038) and IL-6 (adj. p=0.006) levels in patients in remission were significantly lower than those in patients with no remission among the participants with the atypical depression subtype at the eighth-week follow-up. Conclusions: This study provides evidence of differences in inflammatory proteins in patients with varied symptoms among melancholic, atypical and anxious depression subtypes. Further studies on the immunoinflammatory mechanism underlying different subtypes of depression are expected for improved individualised therapy. Trial registration number: NCT03219008.

Progress and challenges in research of the mechanisms of anhedonia in major depressive disorder.

There is an increasing heavy disease burden of major depressive disorder (MDD) globally. Both high diagnostic heterogeneity and complicated pathological mechanisms of MDD pose significant challenges. There is much evidence to support anhedonia as a core feature of MDD. In the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, anhedonia is further emphasised as a key item in the diagnosis of major depression with melancholic features. Anhedonia is a multifaceted symptom that includes deficits in various aspects of reward processing, such as anticipatory anhedonia, consummatory anhedonia, and decision-making anhedonia. Anhedonia is expected to become an important clinicopathological sign for predicting the treatment outcome of MDD and assisting clinical decision making. However, the precise neurobiological mechanisms of anhedonia in MDD are not clearly understood. In this paper, we reviewed (1) the current understanding of the link between anhedonia and MDD; (2) the biological basis of the pathological mechanism of anhedonia in MDD; and (3) challenges in research on the pathological mechanisms of anhedonia in MDD. A more in-depth understanding of anhedonia associated with MDD will improve the diagnosis, prediction, and treatment of patients with MDD in the future.

Major depressive disorder comorbid with general anxiety disorder: Associations among neuroticism, adult stress, and the inflammatory index.

Accumulating evidence shows that higher neuroticism and adult stress may be potential risk factors for major depressive disorder (MDD) comorbid with generalized anxiety disorder (GAD). Studies have shown that anxious and depressed patients have significantly more neurobiological abnormalities than non-anxious depressed patients. However, the biological mechanism of comorbidity remains unknown. A study of serum markers allows a better understanding of the mechanism. This was a multi-centre, cross-sectional study. A total of 169 MDD patients (42 MDD patients with comorbid GAD and 127 MDD patients without comorbid GAD) were studied to analyse the risk factors for MDD with comorbid GAD. Twenty-four peripheral serum markers were measured. Path analysis was applied to test the association among neuroticism, adult stress, inflammatory markers, and psychopathology. After Bonferroni correction, MDD patients with comorbid GAD had lower levels of CCL2 (P = 0.001) and higher levels of α2M (P < 0.001) and TLR-1 (P = 0.001) than MDD patients without comorbid GAD (adjusted P < 0.002). In the path analyses of the association among adult stress, the inflammatory index, and psychopathology, neuroticism had a direct effect (ß = 0.238, P = 0.003) and an indirect effect (ß = 0.068, P = 0.004) on MDD and GAD comorbidity through adult stress and the inflammatory index. Our results suggest that MDD with comorbid GAD is associated with higher levels of inflammatory markers, stress factors and personality traits, which may provide some cues for early identification or more tailored and comprehensive treatment for MDD with comorbid GAD.