Aticaprant, a kappa opioid receptor antagonist, and the recovered 'interest and pleasure' in the concept of major depressive disorder.

Lack of positive mood and anhedonia probably are the most specific depressive symptoms. Anhedonia is a multifaceted concept: the clinical language describes anticipatory/consummatory anhedonia and sensory/social anhedonia while the cognitive neuroscience language describes readiness for reward, energy expenditure to attain reward, updating reward presence and value. Mounting evidence supports the potential of kappa-opioid receptor (KOR) antagonists as novel pharmacotherapies for major depressive disorder : aticaprant is a potent, selective, short-acting KOR antagonist. The fast-fail approach evaluated the impact of aticaprant on the brain circuitry hypothesized to mediate anhedonia and significantly increased fMRI activation in the ventral striatal activation during reward anticipation as compared to placebo; the aticaprant induced changes in the self-reported psychological measures of anhedonia were rather inconsistent. The recently reported results of a phase 2a randomized, double-blind, placebo-controlled trial investigating the efficacy and safety of aticaprant, co-administered to an oral SSRI/SNRI antidepressant in depressed patients who had an inadequate response to 1 or 2 antidepressants. The improvement from baseline favoured the co-administration of aticaprant over the co-administration of placebo at all time points (during 6 weeks), and this was confirmed by higher response rates with aticaprant. A mid-split of patients with higher or lower than median anhedonia also showed that the patients with higher baseline anhedonia had the largest decrease on the MADRS. Tolerability and safety were reassuring. These promising results of the co-administration of aticaprant to an SSRI/SNRI in depressed patients with prominent anhedonia support he further investigation of aticaprant in larger trials.

Sex moderates the effect of anhedonia on parietal alpha asymmetry.

Anhedonia, a transdiagnostic symptom present in many neuropsychiatric disorders, differs in males and females. Parietal EEG alpha asymmetry is associated with reduced arousal and low positive emotionality, and is, therefore, a promising neurophysiologic biomarker of anhedonia. To date, however, no prior studies have determined whether this measure captures sex differences in anhedonic expression. This preliminary study (N = 36) investigated whether anhedonia severity is associated with EEG resting-state parietal alpha asymmetry in adults and whether sex moderates this relationship. Results showed that there was a significant moderating effect of sex such that, only for females, higher levels of anhedonia were associated with increased parietal alpha asymmetry. These findings suggest that parietal alpha asymmetry is a promising biomarker of anhedonia severity in female adults and reinforces the need to account for sex differences in future research.

Exploring mechanisms of anhedonia in depression through neuroimaging and data-driven approaches.

BACKGROUND: Anhedonia is a core symptom of depression that is closely related to prognosis and treatment outcomes. However, accurate and efficient treatments for anhedonia are lacking, mandating a deeper understanding of the underlying mechanisms. METHODS: A total of 303 patients diagnosed with depression and anhedonia were assessed by the Snaith-Hamilton Pleasure Scale (SHAPS) and magnetic resonance imaging (MRI). The patients were categorized into a low-anhedonia group and a high-anhedonia group using the K-means algorithm. A data-driven approach was used to explore the differences in brain structure and function with different degrees of anhedonia based on MATLAB. A random forest model was used exploratorily to test the predictive ability of differences in brain structure and function on anhedonia in depression. RESULTS: Structural and functional differences were apparent in several brain regions of patients with depression and high-level anhedonia, including in the temporal lobe, paracingulate gyrus, superior frontal gyrus, inferior occipital gyrus, right insular gyrus, and superior parietal lobule. And changes in these brain regions were significantly correlated with scores of SHAPS. CONCLUSIONS: These brain regions may be useful as biomarkers that provide a more objective assessment of anhedonia in depression, laying the foundation for precision medicine in this treatment-resistant, relatively poor prognosis group.

Blunted ventral striatal reactivity to social reward is associated with more severe motivation and pleasure deficits in psychosis.

Among individuals living with psychotic disorders, social impairment is common, debilitating, and challenging to treat. While the roots of this impairment are undoubtedly complex, converging lines of evidence suggest that social motivation and pleasure (MAP) deficits play a key role. Yet most neuroimaging studies have focused on monetary rewards, precluding decisive inferences. Here we leveraged parallel social and monetary incentive delay fMRI paradigms to test whether blunted reactivity to social incentives in the ventral striatum-a key component of the distributed neural circuit mediating appetitive motivation and hedonic pleasure-is associated with more severe MAP symptoms in a transdiagnostic sample enriched for psychosis. To maximize ecological validity and translational relevance, we capitalized on naturalistic audiovisual clips of an established social partner expressing positive feedback. Although both paradigms robustly engaged the ventral striatum, only reactivity to social incentives was associated with clinician-rated MAP deficits. This association remained significant when controlling for other symptoms, binary diagnostic status, or ventral striatum reactivity to monetary incentives. Follow-up analyses suggested that this association predominantly reflects diminished striatal activation during the receipt of social reward. These observations provide a neurobiologically grounded framework for conceptualizing the social-anhedonia symptoms and social impairments that characterize many individuals living with psychotic disorders and underscore the need to establish targeted intervention strategies.

Relationship between anhedonia and psychosocial functioning in post-COVID-19 condition: a post-hoc analysis.

BACKGROUND: Post-COVID-19 condition (PCC), also known as "long COVID," is characterized by persistent symptoms, negatively affecting the well-being of individuals with PCC. Anhedonia (i.e. reduced capacity for pleasure) and compromised psychosocial functioning are notable symptoms in those with PCC. We aimed to provide insights to understand the effects of anhedonia and impaired psychosocial functioning of individuals with PCC. METHODS: This post-hoc analysis used data from an 8-week, double-blind, randomized, placebo-controlled trial which evaluated vortioxetine for cognitive deficits in individuals with PCC (Clinicaltrials.gov Identifier: NCT05047952). A total of 147 eligible participants were randomly assigned to receive vortioxetine or matching placebo over eight weeks of double-blind treatment. Our study investigated the relationship between anhedonia, assessed by the Snaith-Hamilton Pleasure Scale (SHAPS), and psychosocial functioning, measured with the Post-COVID Functional Status (PCFS) scale. The analysis was conducted using a generalized linear model, with adjustments for relevant covariates such as age, sex, education, suspected versus confirmed COVID diagnosis, MDD diagnosis, and alcohol consumption. RESULTS: Of the 147 participants, 143 participants had available baseline data for analysis. We observed that baseline PCFS score was statistically significantly positively correlated to baseline SHAPS score (ß = 0.070, p = 0.045, 95% CI). DISCUSSIONS: Our analysis revealed a significant relationship between measures of anhedonia and psychosocial functioning in adults with PCC. Strategies that aim to improve patient-reported outcomes with PCC need to prioritize the prevention and treatment of hedonic disturbances in patients experiencing PCC.

The chronic unpredictable mild stress (CUMS) Paradigm: Bridging the gap in depression research from bench to bedside.

Depression is a complicated neuropsychiatric condition with an incompletely understoodetiology, making the discovery of effective therapies challenging. Animal models have been crucial in improving our understanding of depression and enabling antidepressant medication development. The CUMS model has significant face validity since it induces fundamental depression symptoms in humans, such as anhedonia, behavioral despair, anxiety, cognitive impairments, and changes in sleep, food, and social behavior. Its construct validity is demonstrated by the dysregulation of neurobiological systems involved in depression, including monoaminergic neurotransmission, the hypothalamic-pituitary-adrenal axis, neuroinflammatory processes, and structural brain alterations. Critically, the model's predictive validity is demonstrated by the reversal of CUMS-induced deficits following treatment with clinically effective antidepressants such as selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, tricyclic antidepressants, and monoamine oxidase inhibitors. This review comprehensivelyassesses the multifarious depressive-like phenotypes in the CUMS model using behavioral paradigms like sucrose preference, forced swim, tail suspension, elevated plus maze, and novel object recognition tests. It investigates the neurobiological mechanisms that underlie CUMS-induced behaviors, including signaling pathways involving tumor necrosis factor-alpha, brain-derived neurotrophic factor and its receptor TrkB, cyclooxygenase-2, glycogen synthase kinase-3 beta, and the kynurenine pathway. This review emphasizes the CUMS model's importance as a translationally relevant tool for unraveling the complex mechanisms underlying depression and facilitating the development of improved and targeted interventions for this debilitating neuropsychiatric disorder by providing a comprehensive overview of its validity, behavioral assessments, and neurobiological underpinnings.

Neural substrates of predicting anhedonia symptoms in major depressive disorder via connectome-based modeling.

MAIN PROBLEM: Anhedonia is a critical diagnostic symptom of major depressive disorder (MDD), being associated with poor prognosis. Understanding the neural mechanisms underlying anhedonia is of great significance for individuals with MDD, and it encourages the search for objective indicators that can reliably identify anhedonia. METHODS: A predictive model used connectome-based predictive modeling (CPM) for anhedonia symptoms was developed by utilizing pre-treatment functional connectivity (FC) data from 59 patients with MDD. Node-based FC analysis was employed to compare differences in FC patterns between melancholic and non-melancholic MDD patients. The support vector machines (SVM) method was then applied for classifying these two subtypes of MDD patients. RESULTS: CPM could successfully predict anhedonia symptoms in MDD patients (positive network: r = 0.4719, p < 0.0020, mean squared error = 23.5125, 5000 iterations). Compared to non-melancholic MDD patients, melancholic MDD patients showed decreased FC between the left cingulate gyrus and the right parahippocampus gyrus (p_bonferroni = 0.0303). This distinct FC pattern effectively discriminated between melancholic and non-melancholic MDD patients, achieving a sensitivity of 93.54%, specificity of 67.86%, and an overall accuracy of 81.36% using the SVM method. CONCLUSIONS: This study successfully established a network model for predicting anhedonia symptoms in MDD based on FC, as well as a classification model to differentiate between melancholic and non-melancholic MDD patients. These findings provide guidance for clinical treatment.

Minimal clinically important change in the MADRS anhedonia factor score: A pooled analysis of open-label studies with vortioxetine in patients with major depressive disorder.

BACKGROUND: It is previously reported that the Montgomery-Åsberg Depression Rating Scale (MADRS) anhedonia factor score is correlated with scales assessing function in patients with major depressive disorder (MDD). METHODS: This was an analysis of a database including 5 long-term, extension studies of prior controlled trials, which evaluated the effects of open-label, maintenance treatment with vortioxetine (5-20 mg/day over 1-year) in adults with MDD. We assessed the association of changes in MADRS anhedonia factor scores with changes in the Clinical Global Impression of Severity (CGI-S), Sheehan Disability scale (SDS), and the SF-36. A minimal clinically important change (MCIC) for MADRS anhedonia factor scores was determined using the CGI-S as anchor. RESULTS: In patients who had completed the prior controlled studies, MADRS anhedonia factor scores continued to improve over 1-year of maintenance treatment (mean ±â€¯SE change from baseline of -6.2 ±â€¯0.2 at Month 12). Change in MADRS anhedonia factors score correlated with change in CGI-S (Week 4, r = 0.71), SDS (Week 24 r = 0.60) and SF-36 domains (Week 24 r = -0.19 to -0.61) scores. Using a 1 level improvement on CGI-S as anchor, the MCIC for MADRS anhedonia factor scores versus baseline were - 4.6 at Week 4, -5.5 at Week 24, and - 5.3 at Week 52. LIMITATIONS: Neither the MADRS scale, nor the primary studies, were specifically designed to assess anhedonia. CONCLUSIONS: These open-label data suggest that patients treated with vortioxetine continued to show clinically relevant improvements in their anhedonia over 1-year of maintenance therapy. Improvements in anhedonia correlated with improvements in measures of functioning and quality of life.

Dimensions of Depressive Symptoms in Young Children: Factor Analysis of the Preschool Feelings Checklist-Scale.

The current study is an investigation of the dimensionality of the Preschool Feelings Checklist-Scale (PFC-S), a caregiver-report questionnaire of early childhood depressive symptom severity. Caregivers of 450 young children, ages 3-8 years (M = 5.62, SD = 0.95; 49% female; 7% Hispanic; 66% White), completed the PFC-S and questionnaires on child emotion regulation and expression and self-reported depressive symptomatology. Confirmatory factor analyses indicated that a one-factor structure did not adequately fit the current PFC-S data. Using exploratory factor analysis, a three-factor structure emerged as interpretable and structurally sound, yielding reliable factors related to social and behavioral anhedonia, emotional and behavioral dysregulation, and excessive guilt and sadness. This factor structure showed configural and scalar invariance across preschool-aged and early middle childhood-aged children as well as children assigned male and female sex at birth. Correlations between the three factors and constructs related to depression suggested preliminary construct validity. The current study provides initial evidence for a multidimensional structure of the PFC-S and improves our understanding of early childhood depressive symptoms.

Minocycline Abrogates Individual Differences in Nerve Injury-Evoked Affective Disturbances in Male Rats and Prevents Associated Supraspinal Neuroinflammation.

Chronic neuropathic pain precipitates a complex range of affective and behavioural disturbances that differ markedly between individuals. While the reasons for differences in pain-related disability are not well understood, supraspinal neuroimmune interactions are implicated. Minocycline has antidepressant effects in humans and attenuates affective disturbances in rodent models of pain, and acts by reducing neuroinflammation in both the spinal cord and brain. Previous studies, however, tend not to investigate how minocycline modulates individual affective responses to nerve injury, or rely on non-naturalistic behavioural paradigms that fail to capture the complexity of rodent behaviour. We investigated the development and resolution of pain-related affective disturbances in nerve-injured male rats by measuring multiple spontaneous ethological endpoints on a longitudinal naturalistic foraging paradigm, and the effect of chronic oral minocycline administration on these changes. Disrupted foraging behaviours appeared in 22% of nerve-injured rats - termed 'affected' rats - and were present at day 14 but partially resolved by day 21 post-injury. Minocycline completely prevented the emergence of an affected subgroup while only partly attenuating mechanical allodynia, dissociating the relationship between pain and affect. This was associated with a lasting downregulation of ΔFosB expression in ventral hippocampal neurons at day 21 post-injury. Markers of microglia-mediated neuroinflammation were not present by day 21, however proinflammatory microglial polarisation was apparent in the medial prefrontal cortex of affected rats and not in CCI minocycline rats. Individual differences in affective disturbances following nerve injury are therefore temporally related to altered microglial morphology and hippocampal neuronal activation, and are abrogated by minocycline.

Prenatal Iodine Intake and Maternal Pregnancy and Postpartum Depressive and Anhedonia Symptoms: Findings from a Multiethnic US Cohort.

Objective: Emerging evidence suggests that essential trace elements, including iodine, play a vital role in depressive disorders. This study investigated whether prenatal dietary iodine intake alone and in combination with supplemental iodine intake during pregnancy were associated with antepartum and postpartum depressive and anhedonia symptoms. Methods: The study population included 837 mothers in the PRogramming of Intergenerational Stress Mechanisms (PRISM) study. The modified BLOCK food frequency questionnaire was used to estimate prenatal dietary and supplemental iodine intake, while the 10-item Edinburg Postpartum Depression Scale (EPDS) ascertained depressive symptoms. Analyses considered the global EPDS score and the anhedonia and depressive symptom subscale scores using dichotomized cutoffs. Logistic regression estimating odds ratios and 95% confidence intervals (CIs) assessed associations of iodine intake in the second trimester of pregnancy and 6-month postpartum depressive and anhedonia symptoms considering dietary intake alone and combined dietary and supplementary intake in separate models. Results: Most women were Black/Hispanic Black (43%) and non-Black Hispanics (35%), with 39% reporting a high school education or less. The median (interquartile range, IQR) dietary and supplemental iodine intake among Black/Hispanic Black (198 (115, 337) µg/day) and non-Black Hispanic women (195 (126, 323) µg/day) was higher than the overall median intake level of 187 (116, 315) µg/day. Relative to the Institute of Medicine recommended iodine intake level of 160-220 µg/day, women with intake levels < 100 µg/day, 100-<160 µg/day, >220-<400 µg/day and ≥400 µg/day had increased adjusted odds of 6-month postpartum anhedonia symptoms (aOR = 1.74 (95% CI: 1.08, 2.79), 1.25 (95% CI: 0.80, 1.99), 1.31 (95% CI: 0.82, 2.10), and 1.47 (95% CI: 0.86, 2.51), respectively). The corresponding estimates for postpartum global depressive symptoms were similar but of smaller magnitude. Conclusions: Prenatal iodine intake, whether below or above the recommended levels for pregnant women, was most strongly associated with greater anhedonia symptoms, particularly in the 6-month postpartum period. Further studies are warranted to corroborate these findings, as dietary and supplemental iodine intake are amenable to intervention.

The Nature of Mental Imagery and Its Relationship With Amotivational Psychopathology in People With Schizophrenia Spectrum Disorders.

Many people with schizophrenia spectrum disorders (SSDs) experience profound amotivation, which is strongly related to anticipatory anhedonia. Yet, the neuropsychological fundamentals of anticipatory anhedonia and amotivation are barely understood, resulting in a lack of effective treatments for these patients. Aberrancies in positive mental imagery may interfere with the anticipation of pleasure and could thus explain anticipatory anhedonia and amotivation. However, the nature of mental imagery and its relationship with amotivational psychopathology in SSD is largely unknown. In this preregistered study, we therefore examined mental imagery characteristics and their relation to anticipatory anhedonia, amotivation, and daily life activity in SSD. TheN = 86 participants included individuals with SSD (n = 43) and demographically matched healthy controls (n = 43). Mental imagery, anticipatory pleasure, amotivation, and activity engagement were assessed with structured interviews and self-report questionnaires. Ecological momentary assessment was used to measure state anticipatory pleasure and activity engagement in daily life (n = 81). Compared to the control group, the SSD group showed comparable quantity, but less vividness of mental imagery. Reduced vividness of mental imagery in SSD was significantly associated with higher anticipatory anhedonia, amotivation, and low activity engagement in cross-sectional and prospective analyses. Reduced mental imagery vividness may cause a lack of internal incentive to seek pleasurable experiences and could explain amotivation. Interventions aiming to improve mental imagery vividness and related anticipatory pleasure responses in SSD may be effective in targeting amotivation.

The Independent Contribution of Positive and Negative Metacognitions About Smoking to Urge to Smoke, Withdrawal Symptoms and Dependence in Smoking-Dependent Men.

Previous research has indicated that various factors, such as psychological distress, distress intolerance, anhedonia, impulsivity and smoking metacognitions, have been individually linked to the urge to smoke, withdrawal symptoms and dependence. However, these factors have not been collectively examined to determine whether smoking metacognitions independently and significantly contribute to these outcomes. Therefore, the aim of this study was to investigate the impact of distress intolerance, anhedonia, impulsivity and smoking metacognitions on the urge to smoke, withdrawal symptoms and dependency in men who are dependent on smoking. A total of 300 smoking-dependent men completed psychological scales and smoking-related measures. The findings of the study indicated that positive metacognitions about emotion regulation significantly predicted the urge to smoke, even when accounting for other significant predictors such as the number of daily cigarettes smoked, psychological distress, anhedonia and impulsivity. Furthermore, positive metacognitions about cognitive regulation were found to be a significant predictor of withdrawal symptoms, independent of other significant predictors such as psychological distress and the urge to smoke. Smoking dependence was predicted by negative metacognitions about uncontrollability beyond other significant predictors, including the number of daily cigarettes smoked and distress intolerance. These results highlight the role of metacognitions about smoking in both short- and long-term clinical outcomes related to smoking. Consequently, addressing such beliefs during treatment for smoking dependence should be an important therapeutic goal.

Astroglial Dysfunctions in Mood Disorders and Rodent Stress Models: Consequences on Behavior and Potential as Treatment Target.

Astrocyte dysfunctions have been consistently observed in patients affected with depression and other psychiatric illnesses. Although over the years our understanding of these changes, their origin, and their consequences on behavior and neuronal function has deepened, many aspects of the role of astroglial dysfunction in major depressive disorder (MDD) and post-traumatic stress disorder (PTSD) remain unknown. In this review, we summarize the known astroglial dysfunctions associated with MDD and PTSD, highlight the impact of chronic stress on specific astroglial functions, and how astroglial dysfunctions are implicated in the expression of depressive- and anxiety-like behaviors, focusing on behavioral consequences of astroglial manipulation on emotion-related and fear-learning behaviors. We also offer a glance at potential astroglial functions that can be targeted for potential antidepressant treatment.

Anhedonia as a potential transdiagnostic phenotype with immune-related changes in recent onset mental health disorders.

BACKGROUND: Chronic low-grade inflammation is observed across mental disorders and is associated with difficult-to-treat-symptoms of anhedonia and functional brain changes - reflecting a potential transdiagnostic dimension. Previous investigations have focused on distinct illness categories in those with enduring illness, with few exploring inflammatory changes. We sought to identify an inflammatory signal and associated brain function underlying anhedonia among young people with recent onset psychosis (ROP) and recent onset depression (ROD). METHOD: Resting-state functional magnetic resonance imaging, inflammatory markers, and anhedonia symptoms were collected from N=108 (M age=26.2[SD 6.2]years; Female =50) participants with ROP (n=53) and ROD (n=55) from the EU-FP7-funded PRONIA study. Time-series were extracted using the Schaefer atlas, defining 100 cortical regions of interest. Using advanced multimodal machine learning, an inflammatory marker model and functional connectivity model were developed to classify an anhedonic group, compared to a normal hedonic group. RESULTS: A repeated nested cross-validation model using inflammatory markers classified normal hedonic and anhedonic ROP/ROD groups with a balanced accuracy (BAC) of 63.9%, and an area under the curve (AUC) of 0.61. The functional connectivity model produced a BAC of 55.2% and an AUC of 0.57. Anhedonic group assignment was driven by higher levels of Interleukin-6, S100B, and Interleukin-1 receptor antagonist, and lower levels of Interferon gamma, in addition to connectivity within the precuneus and posterior cingulate. CONCLUSION: We identified a potential transdiagnostic anhedonic subtype that was accounted for by an inflammatory profile and functional connectivity. Results have implications for anhedonia as an emerging transdiagnostic target across emerging mental disorders.

Chronic ecologically relevant stress effects on reverse-translated touchscreen assays of reward responsivity and attentional processes in male rats: Implications for depression.

Stagnation in the development of novel therapeutic strategies for treatment-resistant depression has encouraged continued interest in improving preclinical methods. One tactic prioritizes the reverse translation of behavioral tasks developed to objectively quantify depressive phenotypes in patient populations for their use in laboratory animals via touchscreen technology. After cross-species concordance in task outcomes under healthy conditions is confirmed, construct validity can be further enhanced by identifying environmental stressors that reliably produce deficits in task performance that resemble those in depressive participants. The present studies characterized in male rats the ability of two chronic ecologically relevant stressors, inescapable ice water or isolated restraint, to produce depressive-like behavioral phenotypes in the Probabilistic Reward Task (PRT) and Psychomotor Vigilance Task (PVT). These tasks previously have been reverse-translated using touchscreen technology for rodents and nonhuman primates to objectively quantify, respectively, reward responsivity (anhedonia) and attentional processes (impaired cognitive function), each of which are core features of major depressive disorder. In the PRT, both inescapable ice water and isolated restraint produced persistent anhedonic phenotypes compared to non-stressed control performance (i.e., significantly blunted response bias for the richly rewarded stimulus). In the PVT, both chronic stressors impaired attentional processing, revealed by increases in titrated reaction times; however, these deficits largely subsided by the end of the chronic condition. Taken together, these findings confirm the ability of reverse-translated touchscreen tasks to effectively generate behavioral phenotypes that exhibit expected deficits in performance outcomes following exposure to chronic ecologically relevant stress. In turn, this approach is well positioned to appraise the ability of candidate therapeutics to attenuate or reverse such behavioral deficits and, thereby, contribute to preclinical medications development for treatment-resistant depression.

Childhood unpredictability is associated with increased risk for long- and short-term depression and anhedonia symptoms following combat deployment.

High unpredictability has emerged as a dimension of early-life adversity that may contribute to a host of deleterious consequences later in life. Early-life unpredictability affects development of limbic and reward circuits in both rodents and humans, with a potential to increase sensitivity to stressors and mood symptoms later in life. Here, we examined the extent to which unpredictability during childhood was associated with changes in mood symptoms (anhedonia and general depression) after two adult life stressors, combat deployment and civilian reintegration, which were assessed ten years apart. We also examined how perceived stress and social support mediated and /or moderated links between childhood unpredictability and mood symptoms. To test these hypotheses, we leveraged the Marine Resiliency Study, a prospective longitudinal study of the effects of combat deployment on mental health in Active-Duty Marines and Navy Corpsman. Participants (N = 273) were assessed for depression and anhedonia before (pre-deployment) and 3-6 months after (acute post-deployment) a combat deployment. Additional assessment of depression and childhood unpredictability were collected 10 years post-deployment (chronic post-deployment). Higher childhood unpredictability was associated with higher anhedonia and general depression at both acute and chronic post-deployment timepoints (ßs ≥ 0.16, ps ≤.007). The relationship between childhood unpredictability and subsequent depression at acute post-deployment was partially mediated by lower social support (b = 0.07, 95% CI [0.03, 0.15]) while depression at chronic post-deployment was fully mediated by a combination of lower social support (b = 0.14, 95% CI [0.07, 0.23]) and higher perceived stress (b = 0.09, 95% CI [0.05, 0.15]). These findings implicate childhood unpredictability as a potential risk factor for depression in adulthood and suggest that increasing the structure and predictability of childhood routines and developing social support interventions after life stressors could be helpful for preventing adult depression.

Ketamine treatment for anhedonia in unipolar and bipolar depression: a systematic review.

Ketamine, an N-methyl-D-aspartate receptor antagonist, is a racemic mixture of esketamine and arketamine used to treat unipolar and bipolar depression. Preliminary reports indicate that it may be beneficial for depressed patients reporting symptoms of anhedonia. In this systematic review we aim to assess and analyze the existing body of evidence regarding the therapeutic effects of ketamine on the domain of anhedonia. Electronic databases (PubMed, APA Psycinfo and Web of Science) were searched from inception to November 2023. Protocol was registered in PROSPERO under the identifier CRD42023476603. A total of twenty-two studies, including four randomized-controlled trials and eighteen open-label trials were included. All studies reported alleviation of anhedonia symptoms following ketamine or esketamine administration, regardless of the number of infusions. Several important limitations were included, first and foremost low number of placebo-controlled randomized-controlled trials. This review indicates a potential anti-anhedonic effect of ketamine in patients with depression. Several trials used neuroimaging techniques which confirm ketamine's effect on functional connectivity correlating with the improvement in anhedonia. Despite considerable variations in methodology and the specific brain regions investigated, these studies collectively point towards ketamine's neuroplastic effects in mitigating anhedonia.

Subcallosal area 25: Its responsivity to the stress hormone cortisol and its opposing effects on appetitive motivation in marmosets.

Aberrant activity in caudal subcallosal anterior cingulate cortex (scACC) is implicated in depression and anxiety symptomatology, with its normalisation a putative biomarker of successful treatment response. The function of scACC in emotion processing and mental health is not fully understood despite its known influence on stress-mediated processes through its rich expression of mineralocorticoid and glucocorticoid receptors. Here we examine the causal interaction between area 25 within scACC (scACC-25) and the stress hormone, cortisol, in the context of anhedonia and anxiety-like behaviour. In addition, the overall role of scACC-25 in hedonic capacity and motivation is investigated under transient pharmacological inactivation and overactivation. The results suggest that a local increase of cortisol in scACC-25 shows a rapid induction of anticipatory anhedonia and increased responsiveness to uncertain threat. Separate inactivation and overactivation of scACC-25 increased and decreased motivation and hedonic capacity, respectively, likely through different underlying mechanisms. Together, these data show that area scACC-25 has a causal role in consummatory and motivational behaviour and produces rapid responses to the stress hormone cortisol, that mediates anhedonia and anxiety-like behaviour.

Understanding the role of early life stress and schizophrenia on anxiety and depressive like outcomes: An experimental study.

BACKGROUND: Adverse experiences due to early life stress (ELS) or parental psychopathology such as schizophrenia (SZ) have a significant implication on individual susceptibility to psychiatric disorders in the future. However, it is not fully understood how ELS affects social-associated behaviors as well as the developing prefrontal cortex (PFC). OBJECTIVE: The aim of this study was to investigate the impact of ELS and ketamine induced schizophrenia like symptoms (KSZ) on anhedonia, social behavior and anxiety-like behavior. METHODS: Male and female Sprague-Dawley rat pups were allocated randomly into eight experimental groups, namely control, gestational stress (GS), GS+KSZ, maternal separation (MS), MS+KSZ pups, KSZ parents, KSZ parents and Pups and KSZ pups only. ELS was induced by subjecting the pups to GS and MS, while schizophrenia like symptoms was induced through subcutaneous administration of ketamine. Behavioral assessment included sucrose preference test (SPT) and elevated plus maze (EPM), followed by dopamine testing and analysis of astrocyte density. Statistical analysis involved ANOVA and post hoc Tukey tests, revealing significant group differences and yielding insights into behavioral and neurodevelopmental impacts. RESULTS: GS, MS, and KSZ (dams) significantly reduced hedonic response and increased anxiety-like responses (p < 0.05). Notably, the presence of normal parental mental health demonstrated a reversal of the observed decline in Glial Fibrillary Acidic Protein-positive astrocytes (GFAP+ astrocytes) (p < 0.05) and a reduction in anxiety levels, implying its potential protective influence on depressive-like symptoms and PFC astrocyte functionality. CONCLUSION: The present study provides empirical evidence supporting the hypothesis that exposure to ELS and KSZ on dams have a significant impact on the on development of anxiety and depressive like symptoms in Sprague Dawley rats, while positive parenting has a reversal effect.