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Pavlovian learning processes are central to the etiology and treatment of anxiety disorders. Anhedonia and related perturbations in reward processes have been implicated in Pavlovian learning. Associations between anhedonia symptoms and neural indices of Pavlovian learning can inform transdiagnostic associations among depressive and anxiety disorders.Participants ages 18 to 19 years (67% female) completed a fear extinction (n = 254) and recall (n = 249) paradigm during functional magnetic resonance imaging. Symptom dimensions of general distress (common to anxiety and depression), fears (more specific to anxiety), and anhedonia-apprehension (more specific to depression) were evaluated. We trained whole-brain multivoxel pattern decoders for anhedonia-apprehension during extinction and extinction recall and tested the decoders' ability to predict anhedonia-apprehension in an external validation sample. Specificity analyses examined effects covarying for general distress and fears. Decoding was repeated within canonical brain networks to highlight candidate neurocircuitry underlying whole-brain effects.Whole-brain decoder training succeeded during both tasks. Prediction of anhedonia-apprehension in the external validation sample was successful for extinction (RResults suggest that patterns of brain activity during extinction, particularly in the cognitive control, default mode, limbic, salience, and visual networks, can be predictive of anhedonia symptoms. Future research should examine associations between anhedonia and extinction, including studies of exposure therapy or positive affect treatments among anhedonic individuals.

Research suggests adolescent depression is increasing and certain adolescents may be uniquely vulnerable. However, limited conceptualizations of identity and time, as well as the reliance on unitary conceptualizations of depression, inhibits a nuanced perspective on these trends. In response, we examined how adolescent depressive symptoms, depressed mood, and anhedonia, vary across intersecting identities over time.Secondary data analysis on the National Survey on Drug Use and Health between 2009 and 2017 was conducted. In total 145,499 nationally representative adolescents (ages 12-17) completed a diagnostic assessment for depression. Lifetime and past year reports of depressive symptoms, depressed mood, and anhedonia were treated as separate variables. A novel, mixed-level model in which participants were nested within identity (defined by one's age, gender, race/ethnicity, poverty level) and time was used to test our aims.Overall, the relation between depression outcomes and identity did not vary over time (p .01). Further, identity's impact on depression was approximately ten-fold that of temporal effects. Multiracial, late adolescent, female adolescents were at particular risk. Findings concerning depressed mood and anhedonia were similar across analyses.All facets of identity (e.g., sexual identity) were not included in the model and a unidimensional measure of poverty may have underestimated its depressogenic influence.Adolescent depression outcomes are mostly consistent across criterial symptom subtypes and time, but vary as a function of identity. Prevention protocols that highlight mechanisms of risk tethered to social identity, and include salient experiences of females, late adolescents, and multiracial youth in particular, need to be prioritized in mental health initiatives.

While inflammation has been implicated in psychopathology, relationships between immune-suppressing processes and psychiatric constructs remain elusive. This study sought to assess whether β(2)-agonist clenbuterol (CBL) would attenuate immune activation in adolescents with mood and anxiety symptoms following ex vivo exposure of whole blood to lipopolysaccharide (LPS). Our focus on adolescents aimed to target a critical developmental period when psychiatric conditions often emerge and prior to chronicity effects. To capture a diverse range of immunologic and symptomatologic phenotypes, we included 97 psychotropic-medication free adolescents with mood and anxiety symptoms and 33 healthy controls. All participants had comprehensive evaluations and dimensional assessments of psychiatric symptoms. Fasting whole-blood samples were collected and stimulated with LPS in the presence and absence of CBL for 6 hours, then analyzed for 41 cytokines, chemokines, and hematopoietic growth factors. Comparison analyses used Bonferroni-corrected nonparametric tests. Levels of nine immune biomarkers—including IL-1RA, IL-1β, IL-6, IP-10, MCP-1, MIP-1α, MIP-1β, TGF-α, and TNF-α—were significantly reduced by CBL treatment compared to LPS alone. Exploratory factor analysis reduced 41 analytes into 5 immune factors in each experimental condition, and their relationships with psychiatric symptoms were examined as a secondary aim. CBL + LPS Factor 4—comprising EGF, PDGF-AA, PDGF-AB/BB, sCD40L, and GRO—significantly correlated with anticipatory and consummatory anhedonia, even after controlling for depression severity. This study supports the possible inhibitory effect of CBL on immune activation. Using a data-driven method, distinctive relationships between CBL-affected immune biomarkers and dimensional anhedonia were reported, further elucidating the role of β(2)-agonism in adolescent affective symptomatology.

There is a growing interest in understanding symptoms of psychological distress, such as anhedonia, not just as related to individual psychological disorders, but transdiagnostically. This broader focus allows for the investigation of the effects of symptoms across disorders, or in non-clinical samples. Previous work has linked anhedonia and risk-taking behavior in clinical samples, though the exploration of this relationship in healthy adolescents and early adults is still a relatively new area of research. The current study explored the relationship between variability in anhedonia and risk-taking behavior by breaking each into separable parts (i.e. anhedonia into deficits in anticipatory and consummatory pleasure; risk-taking into risk propensity, sub-optimal risky behavior, and response to punishment). A sample of 81 university students completed two Chapman scales of anhedonia, the Temporal Experience of Pleasure Scale (TEPS), and the Balloon Analogue Risk Task (BART). Hierarchical linear regression analyses were completed to assess the predictive power of each anhedonia measure on each outcome measure on the BART. TEPS score significantly negatively predicted all three outcome measures, with anticipatory pleasure having more predictive power than consummatory pleasure. Physical anhedonia was also a significant predictor of sub-optimal risky behavior and response to punishment. These findings present a broader and more complex view of the associations between anhedonia and risk than have previously been reported, and merit further study to continue to elucidate how they are related to one another.

Major depressive disorder (MDD) is a clinically heterogenous condition and its treatment should be individualized according to the presence of particular symptom clusters. The aim of this pooled analysis was to investigate the effects of adjunctive brexpiprazole on different symptom clusters in MDD.Data were included from four similarly designed, short-term, randomized, double-blind, placebo-controlled studies of adjunctive brexpiprazole in adults with MDD and inadequate response to 2-4 antidepressant treatments (ADTs), including 1 administered by investigators. Mean changes from baseline and Cohen's d effect sizes (ES) versus placebo were determined for the following Montgomery-Åsberg Depression Rating Scale symptom clusters: core, anhedonia, dysphoria, retardation, vegetative, loss of interest, and lassitude.Over 6 weeks, ADT + brexpiprazole 2 mg (n = 486) showed greater improvement than ADT + placebo (n = 585) for all symptom clusters: core (ES = 0.36; p 0.0001), anhedonia (ES = 0.43; p 0.0001), dysphoria (ES = 0.27; p 0.0001), retardation (ES = 0.32; p 0.0001), vegetative (ES = 0.29; p 0.0001), loss of interest (ES = 0.30; p 0.0001), and lassitude (ES = 0.33; p 0.0001). Improvements of similar magnitude were observed for ADT + brexpiprazole 2-3 mg (n = 770) versus ADT + placebo (n = 788) (ES = 0.24-0.38; all clusters p 0.0001). In most cases, improvement over ADT + placebo was observed from Week 1 onwards.Post hoc analysis with no adjunctive active comparator.Patients receiving adjunctive brexpiprazole versus adjunctive placebo showed improvements across a range of MDD symptom clusters. Improvements appeared early (generally from Week 1) and were maintained over 6 weeks. These data indicate that adjunctive brexpiprazole may benefit multiple subtypes of patient with MDD and inadequate response to ADTs.

Pregnancy is a very complex and highly stressful time in which women become more physically and emotionally vulnerable. Therefore, mothers are more likely to face decreased self-esteem and increased postpartum depression. Despite the high prevalence of postpartum depression, more than 50 % of mothers are undiagnosed or untreated, showing an urgent need to explore an effective preventive strategy. A healthy lifestyle and regular physical activity have been suggested to be associated with an increased quality of life in pregnant and postpartum women. The purpose of this study was to determine whether swimming exercise before and during pregnancy can affect maternal care and postpartum depression-related behaviors in dams. To this end, female NMRI and C57BL/6 J mice were subjected to swimming exercise before conception and throughout pregnancy. On postpartum days 1-2, maternal behavior including nest building, active nursing, and licking/grooming were monitored. A battery of behavioral tests was also used to measure depression-related symptoms including anhedonia- and anxiety-like behavior, social behavior, and behavioral despair. To identify the underlying mechanisms, corticosterone and inflammatory cytokines during late pregnancy, and corticosterone and brain serotonin during the postpartum period were measured in dams. The findings indicated that swimming exercise increased gestational corticosterone, decreased maternal care and brain serotonin, and increased all depression-related behaviors in postpartum C57BL/6 J dams, while only increased licking/grooming and social behavior, and reduced anhedonia-like behavior in postpartum NMRI dams. Taken together, this study suggests that swimming exercise before and during pregnancy could alter maternal care and postpartum depression-like behavior in a strain-dependent manner.

Introduction One aim of characterizing dimensional psychopathology is associating different domains of affective dysfunction with brain circuitry. The functional connectome, as measured by magnetic resonance imaging (fMRI), can be modeled and associated with psychopathology through multiple methods; some methods assess univariate relationships while others summarize broad patterns of activity. It remains unclear whether different dimensions of psychopathology require different representations of the connectome to generate reproducible associations. Methods Patients experiencing anxious misery symptomology (depression, anxiety and trauma; n=192) received resting-state fMRI scans. Three modeling approaches (seed-based correlation analysis [SCA], edgewise regression and Brain Basis Set Modeling [BBS]), each relying on increasingly broader representations of the functional connectome, were used to associate connectivity patterns with six data-driven dimensions of psychopathology: anxiety sensitivity, anxious arousal, rumination, anhedonia, insomnia and negative affect. To protect against overfitting, 50 participants were held-out in a testing dataset, leaving 142 participants as training data. Results Different modeling approaches varied in the extent to which they could model different symptom dimensions: SCA failed to reproducibly model any symptoms, subsets of the connectome (edgewise regression) were sufficient to model insomnia and anxious arousal and broad representations of the entire connectome (BBS) were necessary to model negative affect and ruminative thought. Conclusion These results reveal that different methods of representing the functional connectome differ in the degree they can model different symptom dimensions, highlighting the potential sufficiency of subsets of connections for some dimensions and the necessity of connectome-wide approaches in others.

Reward system dysfunction is evident across neuropsychiatric conditions. Here we present data from a double-blinded pharmaco-fMRI study investigating the triggering of anhedonia and reward circuit activity in women.The hormonal states of pregnancy and parturition were simulated in euthymic women with a history of postpartum depression (PPD+; n = 15) and those without such a history (PPD-; n = 15) by inducing hypogonadism, adding back estradiol and progesterone for 8 weeks ("addback"), and then withdrawing both steroids ("withdrawal"). Anhedonia was assessed using the Inventory of Depression and Anxiety Symptoms (IDAS) during each hormone phase. Those who reported a 30 % or greater increase in IDAS anhedonia, dysphoria, or ill temper during addback or withdrawal, compared with pre-treatment, were identified as hormone sensitive (HS+) and all others were identified as non-hormone sensitive (HS-). The monetary incentive delay (MID) task was administered during fMRI sessions at pre-treatment and during hormone withdrawal to assess brain activation during reward anticipation and feedback.On average, anhedonia increased during addback and withdrawal in PPD+ but not PPD-. During reward feedback, both HS+ (n = 10) and HS- (n = 18) showed decreased activation in clusters in the right putamen (p .031, FWE-corrected) and left postcentral and supramarginal gyri (p .014, FWE-corrected) at the withdrawal scans, relative to pre-treatment scans.A modest sample size, stringent exclusion criteria, and relative lack of diversity in study participants limit the generalizability of results.Although results do not explain differential hormone sensitivity in depression, they demonstrate significant effects of reproductive hormones on reward-related brain function in women.

Depressed individuals experience deficits in emotional reactivity. One well-established theory is the Emotion Context Insensitivity (ECI) theory. To better understand impairments in emotional reactivity, we investigated whether the ECI theory is applicable to anticipatory, consummatory, and remembered affect, in both clinical and subclinical depression.Participants were divided into four groups: Major Depressive Disorder Group (MDD, N = 60), Control Group for MDD (ControlThe MDD group was more insensitive to both monetary reward and loss across most types of affect than was the control group. Compared with the controls, the SD group exhibited lower reactivity in anticipatory positive affect but enhanced reactivity in consummatory positive, anticipatory, and remembered negative affect.Emotional affect was evaluated by subjective ratings, which may lack objectivity. Additionally, laboratory settings and monetary rewards used in this study may cause the results less generalized to daily life and to other types of rewards.The pattern of emotional reactivity in the MDD group was partly consistent with the ECI theory, whereas the SD group showed greater arousal and instability of emotional reactions. These different patterns could facilitate the understanding of emotional reactivity and develop further treatments across the course of depression.

Anhedonia is a core symptom of major depressive disorder (MDD) resulting from maladaptive reward processing. Electroconvulsive therapy (ECT) is an effective treatment for patients with MDD. No previous neuroimaging studies have taken a dimensional approach to assess whether ECT-induced volume changes are specifically related to improvements in anhedonia and positive valence emotional constructs. We aimed to assess the relationship between ECT-induced brain volumetric changes and improvement in anhedonia and reward processing in patients with MDD.We evaluated 15 patients with MDD before and after ECT. We used magnetic resonance imaging, clinical scales (i.e., Quick Inventory of Depressive Symptomatology for syndromal depression severity and Snaith-Hamilton Pleasure Scale for anhedonia) and the Temporal Experience of Pleasure Scale for anticipatory and consummatory experiences of pleasure. We identified 5 regions of interest within the reward circuit and a 6th control region relevant for MDD but not core to the reward system (Brodmann Area 25).Anhedonia, anticipatory and consummatory reward processing improved after ECT. Volume increases within the right reward system separated anhedonia responders and non-responders. Improvement in anticipatory (but not consummatory) reward correlated with increases in volume in hippocampus, amygdala, ventral tegmental area and nucleus accumbens.We evaluated a modest sample size of patients with concurrent pharmacological treatment using a subjective psychometric assessment.We highlight the importance of a dimensional and circuit-based approach to understanding target engagement and the mechanism of action of ECT, with the goal to define symptom- and circuit-specific response biomarkers for device neuromodulation therapies.

The heterogeneity of schizophrenia has been acknowledged for decades because of the diverse presentation of symptoms, illness course, and treatment response noted between individuals diagnosed with the disorder. Cluster analysis has been used as a statistical method to determine whether schizophrenia subgroups might be identified based on symptom heterogeneity. However, there is very limited research examining whether heterogeneity in negative symptoms might be useful in establishing schizophrenia subtypes, particularly research examining newer models of negative symptoms based on five latent constructs including anhedonia, asociality, avolition, blunted affect, and alogia. The Brief Negative Symptom Scale was used to assess the five negative symptoms domains in a sample of 220 outpatients diagnosed with schizophrenia or schizoaffective disorder. Cluster analysis supported a four-cluster solution, comprising clusters of subjects with low negative symptoms (LNS), severe negative symptoms (SNS), and two clusters with moderate negative symptoms, one with predominantly elevated blunted affect (BA) and one with elevated avolition (AV). The LNS, SNS, BA, and AV clusters significantly differed on external validators including clinical characteristics, neurocognition, and functional outcome. Findings suggest that schizophrenia heterogeneity can be parsed according to negative symptom subtypes that have distinct clinical and neuropsychological profiles. Implications for diagnosis and treatment are discussed.

BACKGROUND: Current pharmaceutical treatments for depression are sometimes ineffective and may have unwanted side effects that interfere with patient compliance. This study examined the potential antidepressant-like effects of dietary- and microbial-derived aryl hydrocarbon receptor (AhR) ligands, 3,3′-diindolylmethane (DIM) and 1,4-dihydroxy-2-naphthoic acid (1,4-DHNA). METHODS: Female C57BL/6 mice were subjected to unpredictable chronic mild stress (UCMS) or were unstressed. For three weeks prior to UCMS mice were fed daily with vehicle or 20 mg/kg DIM, 1,4-DHNA or AhR-inactive isomer 3,7-DHNA; another group was subjected to two weeks UCMS before ligand administration began. Mice were examined for anhedonia-like behavior as measured by the sucrose preference test. Additionally, anxiety levels of the mice were examined before UCMS and ligand administration began and at the end in the open field, light/dark, elevated plus maze, novelty-induced hypophagia, and marble burying tests. At the end of the experiment they were also examined in the Morris water maze (MWM) task. RESULTS: Both DIM and 1,4-DHNA, but not 3,7-DHNA, successfully prevented and reversed UCMS-induced anhedonia-like behavior. Furthermore, both DIM and DHNA had little to no effect on anxiety levels and did not induce spatial learning deficits. LIMITATIONS: Additional studies are required to determine to what degree the antidepressant-like effects of DIM and 1,4-DHNA can be attributed to their activities as AhR ligands. CONCLUSIONS: Our findings indicate that dietary and microbial-derived AhR ligands may have clinical applications as potential antidepressants. Future studies are necessary to elucidate the role of AhR in depression-like states and the underlying mechanisms of action.

This study was to investigate the relationship between the ventral caudate connectivity and anhedonia. Nineteen depressed patients and 16 healthy controls participated in two identical functional magnetic resonance imaging scans during a 1-year period to determine the resting-state functional connectivity changes using a seed-based approach. Patients showed increased left ventral caudate functional connectivity with superior frontal gyrus over time and the increased connectivity was associated with anhedonia improvement. None of these associations were observed in healthy controls. The findings suggest that left ventral caudate may serve as a potential target to improve the severity of anhedonia.

Background Cannabis remains one of the most widely abused drugs during pregnancy. In utero exposure to its principal psychoactive component, Δ9-tetrahydrocannabinol (THC), can result in long-term neuropsychiatric risk for the progeny. The current study investigated epigenetic signatures underlying these enduring consequences. Methods Rat dams were exposed daily to THC (0.15mg/kg) during pregnancy and adult male offspring were examined for reward and depressive-like behavioral endophenotypes. Using unbiased sequencing approaches, we explored transcriptional and epigenetic profiles in the nucleus accumbens (NAc), a brain area central to reward and emotional processing. An in vitro CRISPRa model coupled with RNA-sequencing was also applied to study specific consequences of epigenetic dysregulation and altered molecular signatures were compared to human major depressive disorder (MDD) transcriptome datasets. Results Prenatal THC-exposure induced increased motivation for food, heightened learned helplessness and anhedonia, and altered stress sensitivity. We identified a robust increase specific to males in the expression of Histone-Lysine N-Methyltransferase 2A (Kmt2a) that targets lysine 4 on histone H3 (H3K4me) in cellular chromatin. Normalizing Kmt2a in the NAc restored the motivational phenotype of prenatally THC-exposed animals. Comparison of RNA and H3K4me3 sequencing datasets from the NAc of rat offspring with the in vitro model of Kmt2a upregulation revealed overlapping, significant disturbances in pathways that mediate synaptic plasticity. Similar epigenetic alterations were detected in human MDD. Conclusions These studies provide direct evidence for the persistent effects of prenatal cannabis exposure on transcriptional and epigenetic deviations in the NAc via Kmt2a dysregulation and associated psychiatric vulnerability.

Background Individuals with insomnia are a subpopulation at high-risk of suicide. However, despite the elements in favour of an implication of anhedonia in the occurrence of current suicidal ideations (SI), no study has investigated the role played by this affective symptom in the occurrence of current SI in individuals with insomnia. The aim of this study was to investigate the risk of current SI associated with lifelong anhedonia and recent change of anhedonia in individuals with insomnia. Method Demographic and polysomnographic data from 493 individuals with insomnia selected retrospectively from the clinical database of the Erasme Hospital Sleep Laboratory were analysed. Current SI were considered present if the score in item 9 of the Beck Depression Inventory (BDI-II) was ≥1 and/or if they were highlighted during the systematic psychiatric assessment conducted on admission to the Sleep Laboratory. Logistic regression analyses were used to determine the risk of current SI associated with anhedonia in individuals with insomnia. Results The prevalence of current SI was 21.5% in our sample of individuals with insomnia. After adjusting for major confounding factors, multivariate logistic regression analyses demonstrated that unlike lifelong anhedonia, only recent change of anhedonia was a risk factor for current SI in individuals with insomnia. Conclusion In this study, we demonstrated that in individuals with insomnia, recent change of anhedonia is a risk factor for current SI, which seems to justify more systematic research and adequate therapeutic management of this condition to allow better prevention in this particular subpopulation at high-risk of suicide.

BACKGROUND: Left frontal alpha oscillations are associated with decreased approach motivation and have been proposed as a target for non-invasive brain stimulation for the treatment of depression and anhedonia. Indeed, transcranial alternating current stimulation (tACS) at the alpha frequency reduced left frontal alpha power and was associated with a higher response rate than placebo stimulation in patients with major depressive disorder (MDD) in a recent double-blind placebo controlled clinical trial. METHODS: In this current study, we aimed to replicate successful target engagement by delineating the effects of a single session of bifrontal tACS at the individualized alpha frequency (IAF-tACS) on alpha oscillations in patients with MDD. 84 participants were randomized to receive verum or sham IAF-tACS. Electrical brain activity was recorded during rest and while viewing emotionally-salient images before and after stimulation to investigate if the modulation of alpha oscillation by tACS exhibited specificity with regards to valence. RESULTS: In agreement with the previous study of tACS in MDD, we found that a single session of bifrontal IAF-tACS reduced left frontal alpha power during the resting state when compared to placebo. Furthermore, the reduction of left frontal alpha oscillation by tACS was specific for stimuli with positive valence. In contrast, these effects on left frontal alpha power were not found in healthy control participants. CONCLUSION: Together these results support an important role of tACS in reducing left frontal alpha oscillations as a future treatment for MDD. NATIONAL CLINICAL TRIAL: NCT03449979, “Single Session of tACS in a Depressive Episode (SSDE)” https://www.clinicaltrials.gov/ct2/show/NCT03449979

BACKGROUND: Anhedonia - a key symptom of depression - is highly associated with poorer outcomes and suicidal behavior. Alterations in the circuitry of reward-related brain regions have been robustly associated with anhedonia in unipolar depression, but not bipolar disorder (BD). We investigated white matter microstructures associated with anhedonia in participants with BD types I and II and first-degree relatives of patients with BD (BD-siblings). METHODS: Eighty participants (BD types I and II: 56 [70%], and BD-siblings: 24 [30%]) underwent diffusion tensor imaging (DTI); Fractional anisotropy (FA) of different tracts were computed. Anhedonia was assessed using item 8, (“inability to feel”) of the MADRS scale. General linear models were used to compare the FA of different tracts in participants with and without anhedonia controlling for several clinical and demographic variables. RESULTS: The mean age of the sample was 37 (±11) years old, and 68.8% were female. Participants with anhedonia (32.5%) presented lower mean FA in the left uncinate fasciculus (UF) (p=0.005), right temporal endings of the superior longitudinal fasciculus (SLFT) (p=0.04), and in the left and right parietal endings of the superior longitudinal fasciculus (SLFP) (p=0.003, and p=0.04, respectively). Similar comparisons between participants with or without current depressive episodes and between participants with or without inner tension according to the MADRS did not show significant differences, specificity of the findings for anhedonia. CONCLUSIONS: Lower FA in the left UF and SLF are potential neuroimaging markers of anhedonia in individuals with BD and high-risk for BD.

Anhedonia is a common, persistent, and disabling phenomenon in patients with major depressive disorder (MDD) and bipolar depression (BD). This study was conducted to investigate the comparative effectiveness of repeated ketamine infusions in treating anhedonia in Chinese individuals suffering from MDD and BD.Ninety-seven individuals suffering from MDD (n = 77) or BD (n = 20) were treated with six intravenous infusions of ketamine (0.5 mg/kg) administered over 40 min. Anhedonia was measured through the Montgomery-Åsberg Depression Rating Scale (MADRS). The antianhedonic response and remission were defined as ≥ 50% and ≥ 75% reduction in MADRS anhedonia subscale score one day after the sixth infusion, respectively.Anti-anhedonic response and remission rates after the sixth ketamine infusion were 48.5% (95% confidence interval = 38.3%-58.6%) and 30.9% (95% confidence interval = 21.6%-40.3%), respectively. When compared to baseline, a significant reduction in the MADRS anhedonia subscale score was observed at 4 h after the first infusion and was maintained with repeated infusions at any time point (all Ps 0.05). The anti-anhedonic effect of ketamine did not differ between the MDD and BD groups.This preliminary study found that repeated ketamine infusions appeared to be effective at rapidly ameliorating anhedonia, with similar efficacy in MDD and BD.

Objective Although depression and anxiety often have distinct etiologies, they frequently co-occur in adolescence. Recent initiatives have underscored the importance of developing new ways of classifying mental illness based on underlying neural dimensions that cut across traditional diagnostic boundaries. Accordingly, the aim of the study was to clarify reward-related neural circuitry that may characterize depressed–anxious youth. Method The Boston Adolescent Neuroimaging of Depression and Anxiety Human Connectome Project tested group differences regarding subcortical volume and nucleus accumbens activation during an incentive processing task among 14- to 17-year-old adolescents presenting with a primary depressive and/or anxiety disorder (n = 129) or no lifetime history of mental disorders (n = 64). In addition, multimodal modeling examined predictors of depression and anxiety symptom change over a 6-month follow-up period. Results Our findings highlighted considerable convergence. Relative to healthy youth, depressed–anxious adolescents exhibited reduced nucleus accumbens volume and activation following reward receipt. These findings remained when removing all medicated participants (∼59% of depressed–anxious youth). Subgroup analyses comparing anxious-only, depressed–anxious, and healthy youth also were largely consistent. Multimodal modeling showed that only structural alterations predicted depressive symptoms over time. Conclusion Multimodal findings highlight alterations within nucleus accumbens structure and function that characterize depressed–anxious adolescents. In the current hypothesis-driven analyses, however, only reduced nucleus accumbens volume predicted depressive symptoms over time. An important next step will be to clarify why structural alterations have an impact on reward-related processes and associated symptoms.

BACKGROUND: Anhedonia has long been theorized to be a multidimensional construct, focusing on domains of reward stimuli and temporal relationship to reward. However, little empirical work has directly examined whether there is support for this assertion. METHODS: The study used data from young adults from four independent samples (n = 2098). Participants completed multiple measures of anhedonia. RESULTS: We used rigorous conducted exploratory and confirmatory factor analyses on items from six commonly used anhedonia measures to examine dimensions underlying anhedonia. Results suggested a four-factor solution with factors reflecting social reward, social disinterest, status/achievement, and physical/natural reward. The identified factors reflected broad content domains of pleasure, but not specific reward processes. The four factors were modestly associated with one another, suggesting a weak common underlying anhedonia trait that manifests across multiple dimensions. Factor scores were associated with personality measures, reward-related indices, and depression symptoms, supporting the validity of the factors. LIMITATIONS: Participants were all young adults and we assessed anhedonia only at the level of self-report. CONCLUSION: Anhedonia is a multidimensional construct. However, the dimensions of anhedonia only distinguish domains of, but not temporal processes of anhedonia. Future work should continue to refine the structures underlying the construct of anhedonia through iterative theory- and data-driven research and examine associations between anhedonia and clinical outcomes.

Background The anterior cingulate cortex (ACC) is a crucial region in the pathophysiology of major depressive disorder (MDD). However, the relationship between functional alterations of the ACC subregions, anhedonia and sleep quality remains unclear in MDD patients. Methods The resting-state functional connectivity (rsFC) of ACC subregions was measured in 41 first-episode medication-naive MDD patients and 63 healthy controls who underwent functional magnetic resonance imaging. Between-group differences were examined using two-sample t-test. Furthermore, correlation and mediation analyses were carried out to investigate the relationships between the aberrant rsFC of ACC subregions, anhedonia and sleep quality in the patients and controls. Results Compared to healthy controls, the MDD patients exhibited increased rsFC of ACC subregions to areas of the anterior default mode network (DMN) and showed decreased rsFC of the right subgenual ACC to left precuneus (PCUN), which belongs to the posterior DMN. In MDD group, the sleep quality and consummatory anhedonia are correlated with some rsFC, which involves the angular gyrus (ANG) and superior frontal gyrus (SFG). More importantly, the rsFC between the right perigenual ACC and left SPG mediates the association between anhedonia and sleep quality in MDD. Limitations The cross-sectional design and the subjective questionaries for assessment. Conclusion These findings confirm the functional alterations of the ACC subregions and reveal the mediating role of ACC subregions in sleep and reward dysfunction in MDD.

Recent models propose reward system dysfunction as a key mediator of the relationship between sleep and depression and anhedonia. This study explored interrelationships among sleep disturbance, depressive symptoms, anhedonia, and reward responsiveness. Two-hundred and sixty undergraduate students completed questionnaires and a daily diary paradigm assessing sleep, reward responsiveness, depression, anhedonia, and positive affect over 1 week. Baseline sleep disturbance was associated with depressive symptoms, anhedonia, and reward responsiveness. Daily diary sleep parameters showed differential associations with anticipatory versus consummatory reward responsiveness and positive affect. Poorer sleep quality, shorter sleep duration, and longer awakening after sleep onset predicted blunted anticipatory and consummatory reward responsiveness, while increased sleep onset latency and lower sleep efficiency predicted only decreased consummatory reward responsiveness. All sleep indices, except sleep onset latency, were associated with positive affect. Findings demonstrate unique associations between disparate sleep disturbance and reward responsiveness elements, highlighting new treatment mechanisms for anhedonia and depression.

Background Individuals with depression often demonstrate an altered peripheral inflammatory profile, as well as emotion perception difficulties. However, correlations of inflammation with overall depression severity are inconsistent and inflammation may only contribute to specific symptoms. Moreover, measurement of the association between inflammation and emotion perception is sparse in adolescence, despite representing a formative window of emotional development and high-risk period for depression onset. Methods Serum interleukin (IL)-6, tumor necrosis factor (TNF)-α, and IL-1β were measured in 34 adolescents aged 12-17 with DSM-IV depressive disorders (DEP) and 29 healthy controls (HC). Participants were evaluated using the Children's Depression Rating Scale-Revised (CDRS-R) and symptom subscales were extracted based on factor analysis. Participants also completed a performance-based measure of emotion perception, the Facial Emotion Perception Test (FEPT), which assesses the accuracy of categorizing angry, fearful, sad, happy, and neutral facial emotions. Results IL-6 and TNF-α correlated with reported depressed mood and somatic symptoms, respectively, but not total CDRS-R score, anhedonia or observed mood, across both DEP and HC. DEP demonstrated lower accuracy for identifying angry facial expressions. Higher IL-6 was inversely related to accuracy and discrimination of angry and neutral faces across all participants. IL-1β was associated with reduced discrimination of fearful faces. Conclusions Inflammatory markers were sensitive to affective and somatic symptoms of depression and processing of emotional threat in adolescents. In particular, IL-6 was elevated in depressed adolescents and therefore may represent a specific target for modulating depressive symptoms and emotion processing

Background Patients with major depressive disorder (MDD) exhibit a diminished ability to think or concentrate, indecisiveness, and altered sensitivity to reward and punishment. These impairments can influence complex risk-related decision-making in dynamic environments. The neurophysiological mechanisms mediating MDD effects on decision-making behavior are not well understood. Methods Patients with MDD (N=50) and healthy controls (HC, N=40) were enrolled. They completed a series of psychometric tests. Event-related potentials (ERPs) were recorded during the performance of a well-validated modified version of Balloon Analogue Risk Task (BART). Results BART behavior data were similar across the two groups except the MDD patients showed more stability of risk aversion. Neurophysiologically, BART losses generated larger P3 amplitudes than wins, and MDD patients had larger feedback-related negativity (FRN) components than HCs in response to negative feedback (losses). Greater FRN amplitudes in response to losses correlated with higher levels of depressiveness, psychological pain, and anhedonia. A longer FRN latency in MDD patients was associated with more severe suicidal ideation. Limitations The findings are based on cross-sectional data, which are not powerful enough to make causal inferences. Conclusion MDD patients exhibit enhanced FRNs in the frontocentral region after receiving negative feedback in a risky decision-making task. FRN magnitude is associated with depressive symptom severity. Punishment hypersensitivity may contribute to the maintenance of depressive symptoms in MDD patients, and FRN may be a useful index of such hypersensitivity.

Background: Previous research has found deficits in both the reward positivity (RewP) and P300 components of the event-related potential (ERP) in relation to depression. The current study examined whether the P300, elicited from imperative stimuli in a gambling task, relates to depression – and can be utilized in tandem with the RewP to better account for individual differences in depression. Methods: In the current study, 80 adults with current depression (Mage = 39.65, 79% female) and 43 healthy controls (Mage = 37.02, 81% female) completed clinical interviews, self-report questionnaires, and the doors gambling task while EEG was recorded. Results: Results indicated a reduced P300 to doors stimuli (i.e., doors P300) in depression, especially among depressed individuals reporting heightened anhedonia. Gain and loss feedback P300s did not differ between groups. Moreover, the doors P300 moderated the association between RewP and depression status: individuals with relatively intact reward processing (i.e., larger RewP) were more likely to be currently depressed if they exhibited a reduced P300. Limitations: The majority of the sample identified as Caucasian which reduces generalizability of current results. Additionally, the current study is cross sectional design which limits insight into how these ERPs coincide with changes in the disorder. Conclusions: The current study demonstrates that a novel P300 component to the doors stimulus appears to be blunted in currently depressed individuals, and that using the doors P300 in combination with the RewP accounts for significantly more variance in depression.

Depression is associated with taste disorders; however, the mechanisms by which mental stress affects taste perception are not well understood. This study aimed to elucidate the effects of psychosocial stress on peripheral taste-sensing systems using a mouse depression model. Male mice were subjected to subchronic and mild social defeat stress (sCSDS). Results showed that sCSDS significantly increased body weight, food and water intake, and social avoidance behavior and that sCSDS did not change reward-seeking behavior on sucrose preference but tended to decrease pheromonal preference for female urine. Furthermore, sCSDS downregulated the mRNA levels of sweet and umami taste receptor subunits, i.e., sweet taste receptor type 1 members 2 and 3 (T1R2 and T1R3), but not the umami taste receptor subunit, i.e., taste receptor type 1 member 1 (T1R1), in the circumvallate papillae of mice. It is known that sucrose preference is mediated by the gut–brain axis without taste perception; thus, it was considered that sCSDS affected the peripheral taste-sensing systems, rather than the central reward systems, which mediate sucrose preference. This is the first study to report that psychosocial stress affects peripheral sweet and umami taste-sensing systems.

Background Schizophrenia is associated with elevated levels of circulating C-reactive protein (CRP) and other inflammatory markers, but it is unclear whether these associations extend to psychotic symptoms occurring in adolescence in the general population. A symptom-based approach may provide important clues for apparent trans-diagnostic effect of inflammation, which is also associated with depression and other psychiatric disorders. Methods Based on data from 2421 participants from the Avon Longitudinal Study of Parents and Children birth cohort, we examined associations of serum CRP levels assessed around age 16 with ten positive and ten negative symptoms of psychosis assessed using questionnaires around age 17, using both individual symptoms and symptom dimension scores as outcomes. Regression models were adjusted for sex, body mass index, depressive symptoms, substance use, and other potential confounders. Results Most prevalent positive symptoms were paranoid ideation (4.8%), visual (4.3%) and auditory (3.5%) hallucinations. Negative symptoms were more strongly correlated with concurrent depressive symptoms (r=0.51; P, Highlights • We examined psychotic symptoms in adolescents from a population-based birth cohort. • Common positive symptoms were paranoid ideation, visual and auditory hallucinations. • Negative symptoms were correlated with depressive and positive symptoms. • CRP was similarly associated with positive and negative symptom dimension scores. • CRP was specifically associated with auditory hallucinations and anhedonia.

Although the relationship between subjective well-being (SWB) and suicidal ideation (SI) has been illustrated in previous research, few studies have conceptualized SWB as a comprehensive measure of life satisfaction in multiple domains, nor have they considered possible mediators such as depressive symptoms. Therefore, the present study aimed to identify dimensions of SWB correlated with SI, and to analyze associations among SWB sub-domains, depressive symptoms, and SI in a community population. A total of 1200 community adults in South Korea, aged 20-86 years, completed self-report questionnaires on demographics, depressive mood (Patient Health Questionnaire-9 [PHQ-9]), SI (item 9 of the PHQ-9), and 14 SWB sub-domains (Subjective Well-Being Inventory). Factors associated with SI, and interactions among SI, depressive mood, and SWB, were identified by logistic regression and phenotype network analyses, respectively. The five main factors influencing the regularized partial correlation network were life satisfaction, self-blame, job, hopelessness, and fatigue. Pathways were observed from work-life balance and life satisfaction to hopelessness; from self-blame and fatigue to safety and health; and from sleep disturbance, concentration difficulties, self-blame, and hopelessness to SI. Making job activities more emotionally rewarding, the potential for career progression and regular work hours could address anhedonia, hopelessness and sleep disturbance, respectively, thus enhancing SWB and reducing SI in the community population.

Background We aimed to examine the occurrence of major depressive disorder (MDD) in a population-based youth sample, assessing both categorical and dimensional presentations of the disorder and its clinical and sociodemographic correlates. Methods We analyzed cross-sectional data from the latest assessment of the 1993 Pelotas Birth Cohort (n = 3,780), a population-based study from Brazil that followed individuals up to age 22 years. We estimated point-prevalence for categorical diagnosis of MDD and comorbid diagnoses using DSM criteria in a structured interview by trained psychologists. Dimensional symptomatology was assessed with the Brazilian Portuguese version of the Center for Epidemiological Studies–Depression Scale–Revised (CES-D-R). Results Point-prevalence of a current unipolar major depressive episode was 2.85% (95%CI 2.37-3.43%). The CES-D-R showed a mean of 9.20 (SD=9.72), with an area under the curve of 0.93 (95%CI 0.91 to 0.95) for the categorical diagnosis of MDD using a cutoff point of 16. Sad mood and somatic symptoms were the most frequent, and also had lower levels of latent values required for endorsement. Sad mood and anhedonia items were the most central items in the network structure. Conclusions In a population-based sample of youths from a middle-income country, MDD prevalence estimates and comorbidity profile were consistent with previous global literature. A focus on symptoms might advance our understanding about MDD among youths by disentangling the heterogeneity of the disorder.

Anhedonia is common in individuals with traumatic experience. Anhedonia symptoms play an important role in posttraumatic psychopathology, and are related to various adverse outcomes. The current study is a preliminary neuroimaging study of the neural correlates of posttraumatic anhedonia symptoms. Resting-state fMRI data were acquired from 88 Chinese earthquake survivors. Whole brain analyses and exploratory ROI-to-ROI analyses were performed to examine the relationship between posttraumatic anhedonia symptoms and resting-state functional connectivity (rsFC) of reward-related subcortical nucleus including nucleus accumbens and ventral pallidum. The rsFC between left ventral pallidum and areas of bilateral posterior cingulate cortex (PCC) and precuneus cortex were found lower in the high posttraumatic anhedonia group, after controlling for sex, age and other posttraumatic stress symptoms. The rsFC between left ventral pallidum and PCC and the rsFC between left ventral pallidum and lateral parietal cortex were significantly lower in the high anhedonia group. Our findings suggest that decreased functional connectivity between the ventral pallidum and the brain default mode network (DMN) regions could be the neural correlates of posttraumatic anhedonia symptoms.

In contrast to the classic models in psychopathology, the network model considers that the temporal interactions between symptoms are the causes of their occurrence. This model could also be particularly suitable for understanding the processes involved in post-stroke depression. The aim of this paper is to perform a network analysis in order to describe the temporal dynamic of the links existing between depression symptoms during the acute phase after stroke. Twenty-five patients (64% male, mean age 58.1±14.9 years old) hospitalized for a minor stroke (no neurocognitive or motor impairment) were involved in an Ecological Momentary Assessment methodology-based study. They used a smartphone application in order to complete four brief questionnaires each day during the week after hospital discharge. The questionnaire included 7-point Likert scales to measure the severity of the following depressive symptoms: sadness, anhedonia, fatigue, diminished concentration ability, negative thoughts on oneself, pessimism. We used Multilevel Vector Autoregressive analysis to describe the temporal links between those symptoms. We used the software R 3.6.0 with the mlVAR package. The p-value was set at .05. The results show two independent symptoms networks. The first one involves the anhedonia, fatigue, negative thoughts on oneself and sadness. It shows that: anhedonia predicts the activation of later fatigue (β=0.135, P=0.037) and later negative thoughts (β=0.152, P=0.019); negative thoughts predict later negative thoughts (β=0.143, P=0.028) and later sadness (β=0.171, P=0.021); fatigue predicts later fatigue (β=0.261, P

Psychological disorders such as major depressive disorder are characterised by interpersonal difficulties and anhedonia. A cognitive mechanism proposed to contribute to the maintenance of these problems is a diminished ability to generate positive mental imagery, especially regarding social interactions. The current study examined whether the effects of social imagery training on social activity and anhedonia could be enhanced with the addition of intranasal oxytocin, and whether these effects might be augmented in persons with a high propensity to engage socially (i.e., high extraversion). University students (N = 111) were randomised to self-administer intranasal oxytocin or placebo, followed by a single session of positive social or non-social imagery training that required participants to imagine 64 positive scenarios occurring in either a social or non-social context, respectively. There were no main effects of imagery type and drug, and no interaction effect on anhedonia and social activity, measured respectively via self-report and a behavioural task. Individuals low in extraversion, trust-altruism, and openness to experience reported significantly more anhedonia after receiving oxytocin relative to placebo, but only following imagery training of positive social outcomes. Results highlight the negative consequences of increasing oxytocin bioavailability after priming social contact in more withdrawn individuals.

Background About every fourth patient with major depressive disorder (MDD) shows evidence of systemic inflammation. Previous studies have shown inflammation-depression associations of multiple serum inflammatory markers and multiple specific depressive symptoms. It remains unclear, however, if these associations extend to genetic/lifetime predisposition to higher inflammatory marker levels and what role metabolic factors such as Body Mass Index (BMI) play. It is also unclear whether inflammation-symptom associations reflect direct or indirect associations, which can be disentangled using network analysis. Methods This study examined associations of polygenic risk scores (PRSs) for immuno-metabolic markers (C-reactive protein [CRP], interleukin [IL]-6, IL-10, tumour necrosis factor [TNF]-α, BMI) with seven depressive symptoms in one general population sample, the UK Biobank study (n = 110,010), and two patient samples, the Munich Antidepressant Response Signature (MARS, n = 1058) and Sequenced Treatment Alternatives to Relieve Depression (STAR*D, n = 1143) studies. Network analysis was applied jointly for these samples using fused graphical least absolute shrinkage and selection operator (FGL) estimation as primary analysis and, individually, using unregularized model search estimation. Stability of results was assessed using bootstrapping and three consistency criteria were defined to appraise robustness and replicability of results across estimation methods, network bootstrapping, and samples. Results Network analysis results displayed to-be-expected PRS-PRS and symptom-symptom associations (termed edges), respectively, that were mostly positive. Using FGL estimation, results further suggested 28, 29, and six PRS-symptom edges in MARS, STAR*D, and UK Biobank samples, respectively. Unregularized model search estimation suggested three PRS-symptom edges in the UK Biobank sample. Applying our consistency criteria to these associations indicated that only the association of higher CRP PRS with greater changes in appetite fulfilled all three criteria. Four additional associations fulfilled at least two consistency criteria; specifically, higher CRP PRS was associated with greater fatigue and reduced anhedonia, higher TNF-α PRS was associated with greater fatigue, and higher BMI PRS with greater changes in appetite and anhedonia. Associations of the BMI PRS with anhedonia, however, showed an inconsistent valence across estimation methods. Conclusions Genetic predisposition to higher systemic inflammatory markers are primarily associated with somatic/neurovegetative symptoms of depression such as changes in appetite and fatigue, consistent with previous studies based on circulating levels of inflammatory markers. We extend these findings by providing evidence that associations are direct (using network analysis) and extend to genetic predisposition to immuno-metabolic markers (using PRSs). Our findings can inform selection of patients with inflammation-related symptoms into clinical trials of immune-modulating drugs for MDD.

Background Intermittent theta burst stimulation (iTBS) over the dorsomedial prefrontal cortex (DMPFC) has shown promise in open-label trials of depression. Methods In this randomized, double-blind, sham controlled trial we evaluate iTBS over the DMPFC for anhedonia, avolition, and blunted affect in patients with schizophrenia or depression. Active iTBS was delivered over the DMPFC with 1200 pulses per session, twice daily over ten weekdays at target intensity with an angled figure-of eight coil. Sham condition comprised the magnetically shielded side of the coil and simultaneous transcutaneous electrical nerve stimulation. Primary outcome was change on the Clinical Assessment Interview for Negative Symptoms (CAINS). Results Twenty-eight patients were randomized to active iTBS and 28 to sham. Mean (standard deviation) change in CAINS score from baseline to the day after last treatment was -5.3 (8.1) in active iTBS and -2.1 (7.1) in sham. A linear model showed no significant effect of treatment, accounting for baseline scores p=.088. Sub analyses per diagnostic group showed a significant effect in patients with depression, p=.038, but not in the schizophrenia group, p=.850. However, overall depressive symptoms did not change significantly in patients with depression. There were three serious adverse events, all in the sham group. Limitations Possibly too short treatment course and few patients with schizophrenia. Conclusion In this first transdiagnostic randomized controlled trial of iTBS over DMPFC for anhedonia, avolition, and blunted affect it can be concluded that it was generally tolerable and safe but only more effective than sham in the subgroup of patients with depression.

Background Ketamine is a highly effective antidepressant for patients with treatment-resistant major depressive disorder (MDD). Resting-state functional magnetic resonance imaging studies show disruptions of functional connectivity (FC) between limbic regions and resting-state networks (RSNs) in MDD, including the default mode network, central executive network (CEN), and salience network (SN). Here, we investigated whether serial ketamine treatments change FC between limbic structures and RSNs. Methods Patients with MDD (n = 44) were scanned at baseline (time 1 [T1]) and 24 hours after the first (T2) and fourth (T3) infusions of ketamine. Healthy control subjects (n = 50) were scanned at baseline, with a subgroup (n = 17) being rescanned at 2 weeks. Limbic regions included the amygdala and hippocampus, and RSNs included the default mode network, CEN, and SN. Results Ketamine increased right amygdala FC to the right CEN (p = .05), decreased amygdala FC to the left CEN (p = .005) at T2 versus T1 (p = .015), which then increased at T3 versus T2 (p = .002), and decreased left amygdala FC to the SN (p = .016). Decreased left amygdala to SN FC at T2 predicted improvements in anxiety at T3 (p = .006). Ketamine increased right hippocampus FC to the left CEN (p = .001), and this change at T2 predicted decreased anhedonia at T3 (p = .005). Conclusions Ketamine modulates FC between limbic regions and RSNs implicated in MDD. Increases in FC between limbic regions and the CEN suggest that ketamine may be involved in restoring top-down control of emotion processing. FC decreases between the left amygdala and SN suggest that ketamine may ameliorate MDD-related dysconnectivity in these circuits. Early FC changes between limbic regions and RSNs may be predictive of clinical improvements.

Social behaviour requires the brain to efficiently integrate multiple social processes, but it is not clear what neural substrates underlie general social behaviour. While psychosis patients and individuals with subclinical symptoms are characterized by social dysfunction, the neural mechanisms underlying social dysfunctions in schizophrenia spectrum disorders remains unclear. We first constructed a general social brain network (SBN) using resting-state functional connectivity (FC) with regions of interest based on the automatic meta-analysis results from NeuroSynth. We then examined the general SBN and its relationship with social network (SN) characteristics in 30 individuals with schizophrenia (SCZ) and 33 individuals with social anhedonia (SA). We found that patients with SCZ exhibited deficits in their SN, while SA individuals did not. SCZ patients showed decreased segregation and functional connectivity in their SBN, while SA individuals showed a reversed pattern with increased segregation and functional connectivity of their SBN. Sparse canonical correlation analysis showed that both SCZ patients and SA individuals exhibited reduced correlation between SBN and SN characteristics compared with their corresponding healthy control groups. These preliminary findings suggest that both SCZ and SA participants exhibit abnormality in segregation and functional connectivity within the general SBN and reduced correlation with SN characteristics. These findings could guide the development of non-pharmacological interventions for social dysfunction in SCZ spectrum disorders.

Prior studies indicate that chronic schizophrenia (SZ) is associated with a specific profile of reinforcement learning abnormalities. These impairments are characterized by: 1) reductions in learning rate, and 2) impaired Go learning and intact NoGo learning. Furthermore, each of these deficits are associated with greater severity of negative symptoms, consistent with theoretical perspectives positing that avolition and anhedonia are associated with impaired value representation. However, it is unclear whether these deficits extend to earlier phases of psychotic illness and when individuals are unmedicated. Two studies were conducted to examine reinforcement learning deficits in earlier phases of psychosis and in high risk patients. In study 1, participants included 35 participants with first episode psychosis (FEP) with limited antipsychotic medication exposure and 25 healthy controls (HC). Study 2 included 17 antipsychotic naïve individuals who were at clinical high-risk for psychosis (CHR) (i.e., attenuated psychosis syndrome) and 18 matched healthy controls (HC). In both studies, participants completed the Temporal Utility Integration Task, a measure of probabilistic reinforcement learning that contained Go and NoGo learning blocks. FEP displayed impaired Go and NoGo learning. In contrast, CHR did not display impairments in Go or NoGo learning. Impaired Go learning was not significantly associated with clinical outcomes in the CHR or FEP samples. Findings provide new evidence for areas of spared and impaired reinforcement learning in early phases of psychosis.

In this short review, we describe recent trends from Ecological Momentary Assessment (EMA) research investigating positive affect (PA) in relation to mood disorders. Aside from notable exceptions (e.g., mania), most mood disorders involve relatively lower levels of PA in daily life, often combined with a larger level of variability in PA. In reaction to positive events, studies show a puzzling “mood brightening” effect in individuals with mood disorder symptoms that suggests hyper responsiveness to real-life rewards. Studies into anhedonia (i.e., lack of, or lower levels of PA) suggest that high-arousal PA and anticipatory PA are potential targets for intervention. Despite PA-focused EMA-interventions bear promises of greater therapeutic effectiveness, so far, these promises have not materialized yet.

Existing animal and human research support the causal role of stress in the emergence of anhedonia, and in turn, the influence of anhedonia in social functioning. However, this model has not been tested in relation to psychosis-risk; this literature gap is notable given that both anhedonia and declining social functioning represent key markers of risk of developing a psychotic disorder such as schizophrenia. The current research tested the evidence for this model using structural equation modeling in 240 individuals selected based on a range of psychosis-risk symptomatology from the general community. Results supported this model in comparison with alternative models, and additionally emphasized the direct role of perceived stress in social functioning outcomes. Findings suggest the clinical relevance of targeting early perceptions of stress in individuals meeting psychosis-risk self-report criteria in an effort to prevent subsequent anhedonia and declines in social functioning.

Aims Low mood and anhedonia are the core symptoms of major depressive disorder (MDD). However, there is no established visual analogue scale that measures pervasiveness of both symptoms. We aimed to validate the Maudsley 3-item Visual Analogue Scale (M3VAS) as a measure of core depressive symptoms and suicidality. Methods This is a cross-sectional secondary analysis combining data from two randomised controlled trials covering a broad range of depression severity from euthymia to severe depression. We validated the M3VAS by testing: 1) latent construct domains using factor analysis; 2) internal consistency using Cronbach's alpha; and 3) convergent validity by correlating M3VAS scores against scores on the Quick Inventory of Depressive Symptomatology-16 item (QIDS-SR-16), which is validated for use in clinical trials. Results Of 180 patients in the combined cohort, 177 (98.3%) provided complete data on the M3VAS and QIDS-SR-16. The mean (SD) age was 41.6 (13.0) years and 59.3% were female. Using factor analysis, one eigenvalue above 1 was produced (2.39) that explained 79.6% of the variance, indicating a one-factor model. Cronbach's alpha was 0.87, demonstrating good internal consistency. Total M3VAS scores correlated strongly (r = 0.72, p Limitations This was a cross-sectional study and was not validated against a clinician-rated assessment for depression. Conclusion The M3VAS is a simple, valid instrument for the assessment of core depressive symptoms and suicidality across the depression spectrum. Future studies should test the longitudinal validity of the M3VAS in detecting changes in core depressive symptoms and suicidality over time.

Circadian rhythms disturbance is widely observable in patients with major depression (MD) and is also associated with depression vulnerability. Of them, disturbed melatonin secretion rhythm is particularly relevant to MD and is strongly phase-locked to core body temperature (CBT) rhythm. Here we aim to study the specific role of each melatonin receptor (MT1 and MT2) subtype in melatonin regulation of circadian CBT and its possible relationship with depressive-like behaviors. MT1-/- , MT2-/- and WT (C57BL/6) mice were used. Anhedonia, using the sucrose intake test, circadian CBT, environmental place preference (EPP) conditioning and vulnerability to chronic social defeat stress (CSDS) procedure were studied. Moreover, the antidepressant effects of reboxetine (15 mg/kg/day, i.p.) for three weeks or ketamine (15 mg/kg i.p. every four days, 4 doses in total) were studied. Further, exposure to ultra-mild stress induced by individual housing for several weeks was also studied in these mice. MT2-/- mice showed anhedonia and lower CBT compared to WT and MT1-/-. In addition, while reward exposure raised nocturnal CBT in WT this increase did not take place in MT2-/- mice. Further, MT2-/- mice showed an enhanced vulnerability to stress-induced anhedonia and social avoidance as well as an impaired acquisition of novelty seeking behavior. Both reboxetine and ketamine reverted anhedonia and induced a clear anti-helpless behavior in the tail suspension test (TST). Reboxetine raised CBT in mice and reverted ultra-mild stress-induced anhedonia. Our findings show a primary role for MT2 receptors in the regulation of circadian CBT as well as anhedonia and suggest that these receptors could be involved in depressive disorders associated to disturbed melatonin function.

Background: Depressive disorders have various symptom presentations, which may have complex and dynamic interactions. This study aimed to investigate the network structures underlying the symptoms and to identify the central symptoms of depression in school-aged children. Methods: Participants were a large community sample of elementary school children aged 6 to 12 years (N = 10,233). To assess the depressive symptoms, we utilized the Children's Depression Inventory (CDI). We binarized the scores on the CDI to generate a symptom network using the eLasso method, based on the Ising model. We evaluated the centralities in individual symptoms using the network centrality indices and the associations between symptoms. Results: Of the symptoms, loneliness, self-hatred, school dislike, and low self-esteem were the most central symptoms in the network of depressive symptoms. School work difficulty–school performance decrement, sadness–crying, self-hatred–negative body image, low self-esteem–fight, anhedonia–school dislike, sadness–loneliness, self-deprecation–school work difficulty, and school dislike–lack of friendship had significantly higher edge weight than most edges. The estimated network between the symptoms was robust to stability and accuracy tests. Limitations: Participants were not clinical but community samples, who show lower level of symptoms. Conclusion: The present symptom network analysis provided important insights on various interconnectivities between individual symptoms in childhood depression and on the central symptoms. In addition, our findings presented both similarities and differences with a previous Western study, thus, warranting future cross-cultural studies.

Acute intoxication by organophosphorus anticholinesterases (OPs) has been associated with depression and other neuropsychiatric disorders. We previously reported that adult male rats treated with diisopropylfluorophosphate (2.5 mg/kg, sc) showed acute cholinergic signs followed by changes (increased immobility/decreased swimming) in the forced swim test (a measure of behavioral despair) for at least one month. This study was conducted to evaluate the further persistence of changes in the forced swim test out to 4 months and to compare responses in a sucrose preference test, a measure of anhedonia. Adult male rats were treated with vehicle (peanut oil, 1 mL/kg, sc) or DFP (2.0, 2.25 or 2.5 mg/kg) followed by sacrifice 4 h later for measurement of OP-sensitive serine hydrolases (cholinesterase [ChE], fatty acid amide hydrolase [FAAH], and monoacylglycerol lipase [MAGL]) in hippocampus. Additional rats were treated similarly and evaluated for functional signs of acute toxicity from 30 min to 6 days, and then motor activity, forced swim behavior and sucrose preference at approximately 1 week, 1 month and 4 months after dosing. All dosages of DFP elicited serine hydrolase inhibition (ChE, 92-96 %; FAAH, 46-63 %; MAGL, 26-33 %). Body weight was reduced in all DFP-treated groups during the first two weeks, and lethality was noted with the higher dosages. Involuntary movements were elicited in all DFP treatment groups during the first week, but both time of onset and rate of recovery were dose-related. There was a significant reduction in ambulation at one week after the highest dosage (2.5 mg/kg), but no other significant locomotor changes were noted. Immobility was increased and swimming was decreased in the forced swim test at all three time-points by 2.25 mg/kg DFP, and at 2 of 3 time-points by the other dosages. While length of water deprivation and time after DFP dosing affected sucrose preference, DFP treatment had no main effect. We conclude that the forced swim test (a measure of behavioral despair/coping mechanism for inescapable stress) is a robust and persistent neurobehavioral consequence of acute DFP intoxication while sucrose preference, a measure of anhedonia and a common symptom of major clinical depression, is not affected.

Background Adolescent depression varies considerably in its course. However, there remain no biobehavioral predictors of illness trajectory, and follow-up studies in depressed youth are sparse. Here, we sought to examine whether reward function would predict future clinical outcomes in adolescents with depressive symptoms. We utilized the reward flanker fMRI task to assess brain function during distinct reward processes of anticipation, attainment, and positive prediction error (PPE, i.e. receiving uncertain rewards). Methods Subjects were 29 psychotropic-medication-free adolescents with mood and anxiety symptoms and 14 healthy controls (HC). All had psychiatric evaluations at baseline and approximately 24-month follow-up. Thirty-two participants (10 HC) had usable fMRI data. Correlation and hierarchical regression models examined baseline symptom severity measures as predictors of follow-up clinical outcomes. Whole-brain analyses examined relationships between neural reward processes and follow-up outcomes. Results Clinically, anhedonia, but not irritability, predicted future depression and suicidal ideation. Among reward processes, only baseline neural activation during PPE correlated with follow-up depression and anhedonia severity. Specifically, activation in the left angular gyrus—a component of the default mode network—was associated with future depression, while activation in the dorsal anterior cingulate, operculum, and left insula—key salience and pain network regions—was associated with future anhedonia, even when controlling for baseline anhedonia. Limitations The small sample size and variable follow-up intervals limit the generalizability of conclusions. Conclusions This research suggests that reward dysfunction, indexed by anhedonia, may predict worse clinical trajectories in depressed youth. Adolescents presenting with significant anhedonia should be carefully monitored for illness progression.

Background Dimensions are recommended as replacements for diagnostic categories of depression, but clinicians continue to use categories. Categories are appropriate if major, underlying changes in symptom structure occur above a clinical cut-off on a depression continuum. Methods Cross-sectional surveys of Chinese undergraduates (n = 39,446) 2014–2018 measured self-reported depressive symptoms, associated psychopathology and etiological risk factors using standardised instruments. We created a continuum using PHQ-9 scores and tested linear and extra-linear contrasts in associated psychopathology, and etiology. We carried out latent class analyses (LCA). Results Most symptoms showed linear increase, but depressed mood, anhedonia, and suicidal ideation showed marked increase at the severe end of the continuum. There was extra-linear increase in associated psychotic symptoms, other psychopathology, age, low family income, chronic pain and physical illness, childhood physical and sexual abuse, and neglect. Four LCs corresponding to Melancholic, Severe melancholic, Non-melancholic, and Mild depression were confirmed, but only above a clinical cut-off along the continuum. Etiological risk factors did not differentiate between classes but showed overall dramatic increase in impact above threshold of clinical severity. Limitations Only one self-report instrument was used (PHQ-9) to measure depression and diagnoses were not validated by clinical interviews. Conclusions Categories are necessary to describe the dramatic changes in underlying structure and symptom associations above a clinical threshold of severity. These result from extra-linear impact of etiological risk factors at the severe end of the depression continuum. Although the study confirmed melancholic and non-melancholic subtypes, further investigation should investigate etiological factors that determine this subdivision.

The desire to obtain social rewards (e.g. positive feedback) features prominently in our lives and relationships, and is relevant to understanding psychopathology – where behavior is often impaired. Investigating social rewards within the psychosis-spectrum offers an especially useful opportunity, given the high rates of impaired social functioning and social isolation. The goal of this study was to investigate hedonic experience associated with social reward processing as a potential biomarker for psychosis risk. This study used a task-based functional magnetic resonance imaging (fMRI) paradigm in adolescents at clinical high-risk for the development of psychosis (CHR, n = 19) and healthy unaffected peers (healthy controls – HC, n = 20). Regional activation and connectivity of the ventromedial prefrontal cortex and ventral striatum were examined in response to receiving positive social feedback relative to an ambiguous feedback condition. Expectations of impaired hedonic processes in CHR youth were generally not supported, as there were no group differences in neural response or task-based connectivity. Although interesting relationships were found linking neural reward response and connectivity with social, anticipatory, and consummatory anhedonia in the CHR group, results are difficult to interpret in light of task limitations. We discuss potential implications for future study designs that seek to investigate social reward processing as a biomarker for psychosis risk.

Although impairment in empathy has been reported in schizophrenia spectrum disorders, little is known about the relationship between empathy and schizotypal traits. This study examines this relationship by applying network analysis to a large sample collected at 18-months follow-up in a longitudinal dataset.One thousand four hundred and eighty-six college students were recruited and completed a set of self-reported questionnaires on empathy, schizotypy, depression, anxiety and stress. Networks were constructed by taking the subscale scores of these measures as nodes and partial correlations between each pair of nodes as edges. Network Comparison Tests were performed to investigate the differences between individuals with high and low schizotypy.Cognitive and affective empathy were strongly connected with negative schizotypy in the network. Physical and social anhedonia showed high centrality measured by strength, closeness and betweenness while anxiety and stress showed high expected influence. Predictability ranged from 22.4% (personal distress) to 79.9% (anxiety) with an average of 54.4%. Compared with the low schizotypy group, the high schizotypy group showed higher global strength (S = 0.813, p0.05) and significant differences in network structure (M = 0.531, p0.001) and strength of edges connecting empathy with schizotypy (adjusted ps0.05).Only self-rating scales were used, and disorganized schizotypy was not included.Our findings suggest that the cognitive and affective components of empathy and dimensions of schizotypy are closely related in the general population and their network interactions may play an important role in individuals with high schizotypy.

Introduction Depression and demoralization are highly prevalent among individuals with physical illnesses but their relationship is still unclear. Objective To examine the relationship between clinical features of depression and demoralization with the network approach to psychopathology. Methods Participants were recruited from the medical wards of a University Hospital in Italy. The Demoralization Scale (DS) was used to assess demoralization, while the Patient Health Questionnaire-9 (PHQ-9) to assess depressive symptoms. The structure of the depression-demoralization symptom network was examined and complemented by the analysis of topological overlap and Exploratory Graph Analysis (EGA) to identify the most relevant groupings (communities) of symptoms and their connections. The stability of network models was estimated with bootstrap procedures and results were compared with factor analysis. Results Life feeling pointless, low mood/discouragement, hopelessness and feeling trapped were among the most central features of the network. EGA identified four communities: (1) Neurovegetative Depression, (2) Loss of purpose, (3) Frustrated Isolation and (4) Low mood and morale. Loss of purpose and low mood/morale were largely connected with other communities through anhedonia, hopelessness and items related to isolation and lack of emotional control. Results from EGA displayed good stability and were comparable to those from factor analysis. Limitations Cross-sectional design; sample heterogeneity Conclusions Among general hospital inpatients, features of depression and demoralization are independent, with the exception of low mood and self-reproach. The identification of symptom groupings around entrapment and helplessness may provide a basis for a dimensional characterization of depressed/demoralized patients, with possible implications for treatment.

Social anhedonia has been employed in psychometric high risk studies to identify putative schizotypes. The current study reports three-year longitudinal results from a community study of social anhedonia: the Maryland Longitudinal Study of Schizotypy (MLSS). The initial recruitment for the MLSS involved mailed questionnaire screening of 2434 18-year olds. Baseline and three-year follow-up laboratory assessments were subsequently conducted with individuals identified as being high in social anhedonia (N = 79) and a comparison sample (N = 79). Across the assessments both groups showed maturational improvement on all clinical symptom measures with declining symptom severity at the follow-up compared to baseline and there were no group differences in personality disorder diagnoses at follow-up. However, compared to the control group, over the three-year follow-up individuals in the social anhedonia group were found to have elevated schizophrenia-spectrum personality disorder (Cluster A) characteristics, greater negative symptom characteristics, and lower global functioning. The social anhedonia group also had lower educational attainment, higher unemployment, and higher rates of mental health service utilization than did the control group. Within the social anhedonia group, social support and family relationships were cross-sectionally related to symptom severity at follow-up, although social support and family variables from baseline were not predictive of clinical symptom outcomes at follow-up. Results indicate that social anhedonia is associated with persistent schizophrenia-spectrum symptoms and functional impairment in early adulthood.

Background Both Major Depressive Disorder (MDD) and Primary Insomnia (PI) have been linked to deficiencies in cortical γ-aminobutyric acid (GABA) and glutamate (Glu) thus suggesting a shared neurobiological link between these two conditions. The extent to which comorbid insomnia contributes to GABAergic or glutamatergic deficiencies in MDD remains unclear. Methods We used single-voxel proton magnetic resonance spectroscopy (1H MRS) at 4 Tesla to examine GABA+ and Glu relative to creatine (Cr) in the dorsal anterior cingulate cortex (dACC) and in the parieto-occipital cortex (POC) of 51 non-medicated adults with MDD, 24 adults with Primary Insomnia (PI), and 25 age- and sex-matched good sleeper controls (HC). Measures of depression severity and subjective and objective sleep quality were compared with 1H MRS metabolite measures. Results MDD subjects exhibited a 15% decrease in Glu/Cr in the dACC compared to HC. Within the MDD group, there was a trend inverse correlation between dACC Glu/Cr and anhedonia ratings. We observed no significant association between measures of sleep quality with dACC Glu/Cr in those with MDD. Limitations The protocol and data interpretation would have been enhanced by the recruitment of MDD subjects with a broader range of affect severity and a more comprehensive assessment of clinical features. Conclusions These findings support the role of cortical glutamatergic mechanisms in the pathophysiology of MDD. Insomnia severity did not further contribute to the relative deficiency of glutamatergic measures in MDD.