Longitudinal relationships of cytokines, depression and anhedonia in depressed adolescents.
Brain, behavior, and immunity
BACKGROUND:Depression has been associated with low-grade elevation of plasma cytokines (e.g. interleukin-6, IL-6; tumor necrosis factor alpha, TNFα) in both cross-sectional and longitudinal studies in adults. Preclinical and clinical studies also suggest that IL-6 and TNFα elevation are associated with anhedonia. However, few studies have examined longitudinal relationships between cytokines and depression/anhedonia in clinically depressed samples, particularly adolescents. METHODS:Thirty-six adolescents with a depressive disorder receiving standard-of-care community treatment were assessed at a baseline and a follow-up timepoint. Self-report and clinical measures of depression and anhedonia, along with plasma IL-6 and TNFα levels, were obtained at both timepoints. Baseline cytokine measures were examined in association with baseline and follow-up clinical measures. On an exploratory basis, change in clinical measures over time was examined in relation to change in cytokine levels over time. RESULTS:Higher baseline TNFα levels predicted higher follow-up depression severity after approximately four months (controlling for baseline depression). Higher baseline TNFα levels also associated positively with baseline anhedonia and predicted higher anhedonia at follow-up (controlling for baseline anhedonia). No association was found between change in clinical measures and change in cytokine levels over time. CONCLUSIONS:Among adolescents receiving standard-of-care community treatment for depression, higher levels of TNFα predicted greater depressive symptoms at 4-month follow-up, suggesting this cytokine may be used to help identify patients in need of more intensive treatment. Elevated TNFα levels were also associated with concurrent and future anhedonia symptoms, suggesting a specific mechanism in which TNFα affects depression trajectories. Future studies should examine the relationships between cytokine levels and depression/anhedonia symptoms at multiple timepoints in larger cohorts of depressed adolescents.
10.1016/j.bbi.2020.09.004
Anhedonia and Depressive Disorders.
Clinical psychopharmacology and neuroscience : the official scientific journal of the Korean College of Neuropsychopharmacology
Anhedonia is a core symptom of depression and of several psychiatric disorders. Anhedonia has however expanded from its original definition to encompass a spectrum of reward processing deficits that received much interest in the last decades. It is a relevant risk factor for possible suicidal behaviors, and that it may operate as an independent risk factor for suicidality apart from the episode severity. Anhedonia has also been linked to inflammation with a possible reciprocal deleterious effect on depression. Its neurophysiological bases mainly include alterations in striatal and prefrontal areas, with dopamine being the most involved neurotransmitter. Anhedonia is thought to have a significant genetic component and polygenic risk scores are a possible tool for predicting an individual's risk for developing anhedonia. Traditional antidepressants, such as selective serotonin reuptake inhibitors, showed a limited benefit on anhedonia, also considering their potential pro-anhedonic effect in some subjects. Other treatments may be more effective in treating anhedonia, such as agomelatine, vortioxetine, ketamine and transcranial magnetic stimulation. Psychotherapy is also widely supported, with cognitive-behavioral therapy and behavioral activation both showing benefit. In conclusion, a large body of evidence suggests that anhedonia is, at least partially, independent from depression, therefore it needs careful assessment and targeted treatment.
10.9758/cpn.23.1086
Neural substrates of predicting anhedonia symptoms in major depressive disorder via connectome-based modeling.
CNS neuroscience & therapeutics
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_ = 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.
10.1111/cns.14871
Anhedonia as a central factor in depression: Neural mechanisms revealed from preclinical to clinical evidence.
Wang Shijing,Leri Francesco,Rizvi Sakina J
Progress in neuro-psychopharmacology & biological psychiatry
Anhedonia is one of the core symptoms of major depressive disorder (MDD), which is often inadequately treated by traditional antidepressants. The modern framework of anhedonia extends the definition from impaired consummatory pleasure or interest in rewards to a broad spectrum of deficits that impact functions such as reward anticipation, approach motivation, effort expenditure, reward valuation, expectation, and reward-cue association learning. Substantial preclinical and clinical research has explored the neural basis of reward deficits in the context of depression, and has implicated mesocorticolimbic reward circuitry comprising the nucleus accumbens, ventral pallidum, ventral tegmental area, amygdala, hippocampus, anterior cingulate, insula, orbitofrontal cortex, and other prefrontal cortex regions. Dopamine modulates several reward facets including anticipation, motivation, effort, and learning. As well, serotonin, norepinephrine, opioids, glutamate, Gamma aminobutyric acid (GABA), and acetylcholine are also involved in anhedonia, and medications targeting these systems may also potentially normalize reward processing in depression. Unfortunately, whereas reward anticipation and reward outcome are extensively explored by both preclinical and clinical studies, translational gaps remain in reward motivation, effort, valuation, and learning, where clinical neuroimaging studies are in the early stages. This review aims to synthesize the neurobiological mechanisms underlying anhedonia in MDD uncovered by preclinical and clinical research. The translational difficulties in studying the neural basis of reward are also discussed.
10.1016/j.pnpbp.2021.110289
Understanding the neurobiological basis of anhedonia in major depressive disorder - evidence for reduced neural activation during reward and loss processing.
Journal of psychiatry & neuroscience : JPN
BACKGROUND:Anhedonia is a key symptom of major depressive disorder (MDD). Anhedonia is associated with aberrant reward processing, but whether it might interfere similarly with the neural processing of aversive stimuli, such as monetary loss, remains unknown. We aimed to investigate potential associations between anhedonia and neural response during reward and loss processing in patients with MDD. METHODS:We investigated blood-oxygen-level-dependent response in the orbitofrontal cortex, cingulate cortex, insula and basal ganglia during monetary reward and loss processing in 182 patients with MDD, using a card-guessing paradigm. We measured anhedonia with the Social and Physical Anhedonia Scale (SASPAS), and we tested for the main and interaction effects of SASPAS scores and the experimental condition (reward or loss) in a full factorial model. RESULTS:We detected a negative main effect of anhedonia, as well as a significant interaction effect of anhedonia and the experimental condition, on orbitofrontal and insular neural response. Post hoc analyses revealed that the interaction was driven by a significant association between higher anhedonia scores and hypoactivation during loss processing. We observed no significant association between anhedonia and neural response during reward processing. LIMITATIONS:This study had a cross-sectional design. CONCLUSION:Our findings confirmed that altered neural processing in the orbitofrontal cortex and insula is a neurobiological feature of anhedonic symptomatology in people with MDD. The pronounced association between anhedonia and blunted neural response during loss processing supports a broader concept for the neurobiological basis of anhedonia. Hence, MDD with anhedonic features might be characterized by reduced neural response to external stimuli, potentially because of amotivation.
10.1503/jpn.210180
Neural Indicators of Anhedonia: Predictors and Mechanisms of Treatment Change in a Randomized Clinical Trial in Early Childhood Depression.
Barch Deanna M,Whalen Diana,Gilbert Kirsten,Kelly Danielle,Kappenman Emily S,Hajcak Greg,Luby Joan L
Biological psychiatry
BACKGROUND:Early childhood depression is associated with anhedonia and reduced event-related potential (ERP) responses to rewarding or pleasant stimuli. Whether these neural measures are indicators of target engagement or treatment outcome is not yet known. METHODS:We measured ERP responses to win and loss feedback in a guessing task and to pleasant versus neutral pictures in young (4.0-6.9 years of age) depressed children before and after randomization to either 18 weeks of Parent-Child Interaction Therapy-Emotion Development (PCIT-ED) or waitlist. RESULTS:Analyses included reward positivity (RewP) data from 118 children randomly assigned to PCIT-ED (n = 60) or waitlist (n = 58) at baseline and late positive potential (LPP) data from 99 children (44 assigned to PCIT-ED vs. 55 assigned to waitlist) at baseline. Children undergoing PCIT-ED showed a greater reduction in anhedonia (F = 10.32, p = .002, partial η = .09). RewP reward responses increased more (F = 5.98, p = .02, partial η = .07) for PCIT-ED, but a greater change in RewP was not significantly associated with a greater reduction in major depressive disorder symptoms (r = -.12, p > .4). Baseline RewP did not predict treatment change. LPPs to positive pictures did not change across treatment, but greater baseline LPPs to positive pictures predicted a higher likelihood of remission from major depressive disorder in children undergoing PCIT-ED (B = 0.14; SE = 0.07; odds ratio = 1.15; p = .03). CONCLUSIONS:The ERP reward response improved in young children with depression during a treatment designed to enhance emotion development, providing evidence of target engagement of the neural systems associated with reward. Further, greater baseline LPP responses to positive pictures was associated with a greater likelihood of depression remission, suggesting that this ERP measure can predict which children are most likely to respond to treatment.
10.1016/j.biopsych.2020.06.032
Anhedonia modulates the effects of positive mood induction on reward-related brain activation.
NeuroImage
Blunted activation in the reward circuitry has been associated with anhedonia, the inability to experience pleasure in previously rewarding activities. In healthy individuals, reward-related activation has been found to be modulated by acute contextual factors such as induced positive mood. Accordingly, blunted reward response in anhedonia might involve a failure to appropriately modulate reward-related activation as a function of context. To test this hypothesis, 29 participants (19 females, mean age of 24.14 ± 4.61, age range 18-34), with a wide range of anhedonic symptoms, underwent functional MRI while anticipating and receiving monetary rewards, before and after a positive mood induction. Change in neural activation from before to after mood induction was quantified, and effects of anhedonia were investigated through whole-brain, ROI, and functional connectivity analyses. Contrary to hypotheses, results indicated that during reward anticipation (but not receipt), nucleus accumbens activation decreased while its connectivity with the dorsolateral prefrontal cortex increased, following positive mood induction. Critically, anhedonia modulated both effects. The unexpected finding of decreased activation to reward cues following positive mood induction is compelling as it aligns with a prominent behavioral model of the effect of positive mood on exploration of rewarding and neutral stimuli. Furthermore, the modulation of this effect by anhedonia suggests that it may be a key process altered in anhedonia.
10.1016/j.neuroimage.2019.02.063
The neurobiology of anhedonia and other reward-related deficits.
Der-Avakian Andre,Markou Athina
Trends in neurosciences
Anhedonia, or markedly diminished interest or pleasure, is a hallmark symptom of major depression, schizophrenia and other neuropsychiatric disorders. Over the past three decades, the clinical definition of anhedonia has remained relatively unchanged, although cognitive psychology and behavioral neuroscience have expanded our understanding of other reward-related processes. Here, we review the neural bases of the construct of anhedonia that reflects deficits in hedonic capacity and also closely linked to the constructs of reward valuation, decision-making, anticipation and motivation. The neural circuits subserving these reward-related processes include the ventral striatum, prefrontal cortical regions, and afferent and efferent projections. An understanding of anhedonia and other reward-related constructs will facilitate the diagnosis and treatment of disorders that include reward deficits as key symptoms.
10.1016/j.tins.2011.11.005
Assessing anhedonia in depression: Potentials and pitfalls.
Rizvi Sakina J,Pizzagalli Diego A,Sproule Beth A,Kennedy Sidney H
Neuroscience and biobehavioral reviews
The resurgence of interest in anhedonia within major depression has been fuelled by clinical trials demonstrating its utility in predicting antidepressant response as well as recent conceptualizations focused on the role and manifestation of anhedonia in depression. Historically, anhedonia has been understood as a "loss of pleasure", yet neuropsychological and neurobiological studies reveal a multifaceted reconceptualization that emphasizes different facets of hedonic function, including desire, effort/motivation, anticipation and consummatory pleasure. To ensure generalizability across studies, evaluation of the available subjective and objective methods to assess anhedonia is necessary. The majority of research regarding anhedonia and its neurobiological underpinnings comes from preclinical research, which uses primary reward (e.g. food) to probe hedonic responding. In contrast, behavioural studies in humans primarily use secondary reward (e.g. money) to measure many aspects of reward responding, including delay discounting, response bias, prediction error, probabilistic reversal learning, effort, anticipation and consummatory pleasure. The development of subjective scales to measure anhedonia has also increased in the last decade. This review will assess the current methodology to measure anhedonia, with a focus on scales and behavioural tasks in humans. Limitations of current work and recommendations for future studies are discussed.
10.1016/j.neubiorev.2016.03.004
Treatment for Anhedonia: A Neuroscience Driven Approach.
Craske Michelle G,Meuret Alicia E,Ritz Thomas,Treanor Michael,Dour Halina J
Depression and anxiety
Anhedonia, or loss of interest or pleasure in usual activities, is characteristic of depression, some types of anxiety, as well as substance abuse and schizophrenia. Anhedonia is a predictor of poor long-term outcomes, including suicide, and poor treatment response. Because extant psychological and pharmacological treatments are relatively ineffective for anhedonia, there is an unmet therapeutic need for this high-risk symptom. Current psychological and drug treatments for anxiety and depression focus largely on reducing excesses in negative affect rather than improving deficits in positive affect. Recent advances in affective neuroscience posit that anhedonia is associated with deficits in the appetitive reward system, specifically the anticipation, consumption, and learning of reward. In this paper, we review the evidence for positive affect as a symptom cluster, and its neural underpinnings, and introduce a novel psychological treatment for anxiety and depression that targets appetitive responding. First, we review anhedonia in relation to positive and negative valence systems and current treatment approaches. Second, we discuss the evidence linking anhedonia to biological, experiential, and behavioral deficits in the reward subsystems. Third, we describe the therapeutic approach for Positive Affect Treatment (PAT), an intervention designed to specifically target deficits in reward sensitivity.
10.1002/da.22490