Objective Major depressive disorder (MDD) is characterized by impaired reward processing, possibly due to dysfunction in the basal ganglia. However, few neuroimaging studies of depression have distinguished between anticipatory and consummatory phases of reward processing. Using functional magnetic resonance imaging (fMRI) and a task that dissociates anticipatory and consummatory phases of reward processing, the authors tested the hypothesis that MDD participants would show reduced reward-related responses in basal ganglia structures. Method A monetary incentive delay task was presented to 30 unmedicated MDD subjects and 31 healthy comparison subjects during fMRI scanning. Whole-brain analyses focused on neural responses to reward-predicting cues and rewarding outcomes (i.e., monetary gains). Secondary analyses focused on the relationship between anhedonic symptoms and basal ganglia volumes. Results Relative to comparison subjects, MDD participants showed significantly weaker responses to gains in the left nucleus accumbens and bilateral caudate. Group differences in these regions were specific to rewarding outcomes and did not generalize to neutral or negative outcomes, although relatively reduced responses to monetary penalties in MDD emerged in other caudate regions. By contrast, evidence for group differences during reward anticipation was weaker, although MDD subjects showed reduced activation to reward cues in a small sector of the left posterior putamen. Among MDD subjects, anhedonic symptoms and depression severity were associated with reduced bilateral caudate volume. Conclusions These results indicate that basal ganglia dysfunction in MDD may affect the consummatory phase of reward processing. Additionally, morphometric results suggest that anhedonia in MDD is related to caudate volume.

BackgroundDepression is characterised partly by blunted reactions to reward. However, tasks probing this deficiency have not distinguished insensitivity to reward from insensitivity to the prediction errors for reward that determine learning and are putatively reported by the phasic activity of dopamine neurons. We attempted to disentangle these factors with respect to anhedonia in the context of stress, Major Depressive Disorder (MDD), Bipolar Disorder (BPD) and a dopaminergic challenge.MethodsSix behavioural datasets involving 392 experimental sessions were subjected to a model-based, Bayesian meta-analysis. Participants across all six studies performed a probabilistic reward task that used an asymmetric reinforcement schedule to assess reward learning. Healthy controls were tested under baseline conditions, stress or after receiving the dopamine D2 agonist pramipexole. In addition, participants with current or past MDD or BPD were evaluated. Reinforcement learning models isolated the contributions of variation in reward sensitivity and learning rate.ResultsMDD and anhedonia reduced reward sensitivity more than they affected the learning rate, while a low dose of the dopamine D2 agonist pramipexole showed the opposite pattern. Stress led to a pattern consistent with a mixed effect on reward sensitivity and learning rate.ConclusionReward-related learning reflected at least two partially separable contributions. The first related to phasic prediction error signalling, and was preferentially modulated by a low dose of the dopamine agonist pramipexole. The second related directly to reward sensitivity, and was preferentially reduced in MDD and anhedonia. Stress altered both components. Collectively, these findings highlight the contribution of model-based reinforcement learning meta-analysis for dissecting anhedonic behavior.

These findings indicate that acute stress reduces reward responsiveness, particularly in individuals with anhedonic symptoms. Stress-induced hedonic deficit is a promising candidate mechanism linking stressful experiences to depression.

Summary Background Variation in liability to cannabis use disorder has a strong genetic component (estimated twin and family heritability about 50–70%) and is associated with negative outcomes, including increased risk of psychopathology. The aim of the study was to conduct a large genome-wide association study (GWAS) to identify novel genetic variants associated with cannabis use disorder. Methods To conduct this GWAS meta-analysis of cannabis use disorder and identify associations with genetic loci, we used samples from the Psychiatric Genomics Consortium Substance Use Disorders working group, iPSYCH, and deCODE (20 916 case samples, 363 116 control samples in total), contrasting cannabis use disorder cases with controls. To examine the genetic overlap between cannabis use disorder and 22 traits of interest (chosen because of previously published phenotypic correlations [eg, psychiatric disorders] or hypothesised associations [eg, chronotype] with cannabis use disorder), we used linkage disequilibrium score regression to calculate genetic correlations. Findings We identified two genome-wide significant loci: a novel chromosome 7 locus ( FOXP2 , lead single-nucleotide polymorphism [SNP] rs7783012; odds ratio [OR] 1·11, 95% CI 1·07–1·15, p=1·84 × 10 −9 ) and the previously identified chromosome 8 locus (near CHRNA2 and EPHX2 , lead SNP rs4732724; OR 0·89, 95% CI 0·86–0·93, p=6·46 × 10 −9 ). Cannabis use disorder and cannabis use were genetically correlated ( r g 0·50, p=1·50 × 10 −21 ), but they showed significantly different genetic correlations with 12 of the 22 traits we tested, suggesting at least partially different genetic underpinnings of cannabis use and cannabis use disorder. Cannabis use disorder was positively genetically correlated with other psychopathology, including ADHD, major depression, and schizophrenia. Interpretation These findings support the theory that cannabis use disorder has shared genetic liability with other psychopathology, and there is a distinction between genetic liability to cannabis use and cannabis use disorder. Funding National Institute of Mental Health; National Institute on Alcohol Abuse and Alcoholism; National Institute on Drug Abuse; Center for Genomics and Personalized Medicine and the Centre for Integrative Sequencing; The European Commission, Horizon 2020; National Institute of Child Health and Human Development; Health Research Council of New Zealand; National Institute on Aging; Wellcome Trust Case Control Consortium; UK Research and Innovation Medical Research Council (UKRI MRC); The Brain & Behavior Research Foundation; National Institute on Deafness and Other Communication Disorders; Substance Abuse and Mental Health Serv...

Depression has been linked to increased cortisol reactivity and differences in limbic brain volumes, yet the mechanisms underlying these alterations are unclear. One main hypothesis is that stress causes these effects. This is supported by animal studies showing that chronic stress or glucocorticoid administration can lead to alterations in hippocampal and amygdala structures. Relatedly, life stress is cited as one of the major risk factors for depression and candidate gene studies have related variation in stress-system genes to increased prevalence and severity of depression. The present study tested the hypothesis that genetic profile scores combining variance across 10 single nucleotide polymorphisms from four stress-system genes (CRHR1, NR3C2, NR3C1, and FKBP5) and early life stress would predict increases in cortisol levels during laboratory stressors in 120 preschool-age children (3-5 years old), as well as hippocampal and amygdala volumes assessed with MRI in these same children at school age (7-12 years old). We found that stress-system genetic profile scores positively predicted cortisol levels while the number of stressful/traumatic life events experienced by 3-5 years old negatively predicted cortisol levels. The interaction of genetic profile scores and early life stress predicted left hippocampal and left amygdala volumes. Cortisol partially mediated the effects of genetic variation and life stress on limbic brain volumes, particularly on left amygdala volume. These results suggest that stress-related genetic and early environmental factors contribute to variation in stress cortisol reactivity and limbic brain volumes in children, phenotypes associated with depression in adulthood.