J. F. W. Deakin

The University of Manchester, Manchester, England, United Kingdom

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Publications (232)1292.02 Total impact

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    ABSTRACT: One influential view is that vulnerability to major depressive disorder (MDD) is associated with a proneness to experience negative emotions in general. In contrast, blame attribution theories emphasise the importance of blaming oneself rather than others for negative events. Our previous exploratory study provided support for the attributional hypothesis that patients with remitted MDD show no overall bias towards negative emotions, but a selective bias towards emotions entailing self-blame relative to emotions that entail blaming others. More specifically, we found a decreased proneness for contempt/disgust towards others relative to oneself (i.e. self-contempt bias). Here, we report a definitive test of the competing general negative versus specific attributional bias theories of MDD. We compared a medication-free remitted MDD (n=101) and a control group (n=70) with no family or personal history of MDD on a previously validated experimental test of moral emotions. The task measures proneness to specific emotions associated with different types of self-blame (guilt, shame, self-contempt/disgust, self-indignation/anger) and blame of others (other-indignation/anger, other-contempt/disgust) whilst controlling for the intensity of unpleasantness. We confirmed the hypothesis that patients with MDD exhibit an increased self-contempt bias with a reduction in contempt/disgust towards others. Furthermore, they also showed a decreased proneness for indignation/anger towards others. This corroborates the prediction that vulnerability to MDD is associated with an imbalance of specific self- and other-blaming emotions rather than a general increase in negative emotions. This has important implications for neurocognitive models and calls for novel focussed interventions to rebalance blame in MDD. Copyright © 2015. Published by Elsevier Masson SAS.
  • Arpan Dutta, Shane McKie, J F William Deakin
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    ABSTRACT: The need for rapid acting antidepressants is widely recognised. There has been much interest in glutamate mechanisms in major depressive disorder (MDD) as a promising target for the development of new antidepressants. A single intravenous infusion of ketamine, a N-methyl-d-aspartate (NMDA) receptor antagonist anaesthetic agent, can alleviate depressive symptoms in patients within hours of administration. The mechanism of action appears to be in part through glutamate release onto non-NMDA receptors including α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and metabotropic receptors. However these are also reported effects on 5-HT, dopamine and intracellular effects on the mammalian target of rapamycin (mTOR) pathway. The effects of SSRI (Selective Serotonin Reuptake Inhibitor) antidepressants may also involve alterations in NMDA function. The article reviews the effect of current antidepressants on NMDA and examines the efficacy and mechanism of ketamine. Response to ketamine is also discussed and comparison with other glutamate drugs including lamotrigine, amantadine, riluzole, memantine, traxoprodil, GLYX-13, MK-0657, RO4917523, AZD2066 and Coluracetam. Future studies need to link the rapid antidepressant effects seen with ketamine to inflammatory theories in MDD. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.
    Psychiatry Research 11/2014; DOI:10.1016/j.psychres.2014.10.028 · 2.68 Impact Factor
  • Arpan Dutta, Shane McKie, J.F. William Deakin
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    ABSTRACT: Resting state functional magnetic resonance imaging (fMRI) examines the spontaneous low frequency neural activity of the brain to reveal networks of correlated neural activity. A number of different methodologies, each with its own advantages and disadvantages, have been used to examine networks of neural activity that may be related to clinical presentation. Major depressive disorder (MDD) research has largely focused on the default mode network (DMN), which is most active at rest and may relate to negative rumination. However, other networks can be discerned in the resting state such as salience and affective and cognitive control networks, all of which may be relevant to MDD psychopathology. This article reviews the rapidly increasing literature on resting state networks. A number of state- and trait-dependent abnormalities have been reported in MDD in a wide variety of regions including the cerebellum, lingual gyrus, anterior cingulate cortex (ACC), middle frontal gyrus (MFG), dorsolateral prefrontal cortex (dlPFC), amygdala and insula. Current and chronic medication is often a potential confound. Few trials have examined the immediate or delayed effects of antidepressants on resting state networks. This article presents a novel approach to the analysis of drug effects, the identification of signatures of efficacy, and thus for drug development.
    Psychiatry Research Neuroimaging 10/2014; DOI:10.1016/j.pscychresns.2014.10.003 · 2.83 Impact Factor
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    ABSTRACT: Prosocial emotions related to self-blame are important in guiding human altruistic decisions. These emotions are elevated in major depressive disorder (MDD), such that MDD has been associated with guilt-driven pathological hyper-altruism. However, the impact of such emotional impairments in MDD on different types of social decision-making is unknown.
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    Paul Faulkner, J F William Deakin
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    ABSTRACT: FAULKNER, P. and DEAKIN, J.F.W. The role of serotonin in reward, punishment and behavioural inhibition in humans; insights from studies with acute tryptophan depletion Deakin and Graeff proposed that forebrain 5-hydroxytryptamine (5-HT) projections are activated by aversive events and mediate anticipatory coping responses including avoidance learning and suppression of the fight-flight escape/panic response. Other theories proposed 5-HT mediates aspects of behavioural inhibition or reward. Most of the evidence comes from rodent studies. We review 36 experimental studies in humans in which the technique of acute tryptophan depletion (ATD) was used to explicitly address the role of 5-HT in response inhibition, punishment and reward. ATD did not cause disinhibition of responding in the absence of rewards or punishments (9 studies). A major role for 5-HT in reward processing is unlikely but further tests are warranted by some ATD findings. Remarkably, ATD lessened the ability of punishments (losing points or notional money) to restrain behaviour without affecting reward processing in 7 studies. 2 of these studies strongly indicate that ATD blocks 5-HT mediated aversively conditioned Pavlovian inhibition and this can explain a number of the behavioural effects of ATD.
    Neuroscience & Biobehavioral Reviews 09/2014; 46. DOI:10.1016/j.neubiorev.2014.07.024 · 10.28 Impact Factor
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    ABSTRACT: There is increasing evidence that genetic factors play a role in differential susceptibility to depression in response to severe or chronic adversity. Studies in animals suggest that nitric oxide (NO) signalling plays a key role in depression-like behavioural responses to stress. This study investigated whether genetic variation in the brain-expressed nitric oxide synthase gene NOS1 modifies the relationship between psychosocial stress and current depression score. We recruited a population sample of 1222 individuals who provided DNA and questionnaire data on symptoms and stress. Scores on the List of Life-Threatening Experiences (LTE) questionnaire for the last year and self-rated current financial hardship were used as measures of recent/ongoing psychosocial stress. Twenty SNPs were genotyped. Significant associations between 8 NOS1 SNPs, comprising two regional haplotypes, and current depression score were identified that survived correction for multiple testing when current financial hardship was used as the interaction term. A smaller 3 SNP haplotype (rs10507279, rs1004356, rs3782218) located in a regulatory region of NOS1 showed one of the strongest effects, with the A-C-T haplotype associating with higher depression scores at low adversity levels but lower depression scores at higher adversity levels (p=2.3E-05). These results suggest that NOS1 SNPs interact with exposure to economic and psychosocial stressors to alter individual's susceptibility to depression.Neuropsychopharmacology accepted article preview online, 11 June 2014; doi:10.1038/npp.2014.137.
    Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 06/2014; DOI:10.1038/npp.2014.137 · 8.68 Impact Factor
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    ABSTRACT: Galanin is a stress-inducible neuropeptide and cotransmitter in serotonin and norepinephrine neurons with a possible role in stress-related disorders. Here we report that variants in genes for galanin (GAL) and its receptors (GALR1, GALR2, GALR3), despite their disparate genomic loci, conferred increased risk of depression and anxiety in people who experienced childhood adversity or recent negative life events in a European white population cohort totaling 2,361 from Manchester, United Kingdom and Budapest, Hungary. Bayesian multivariate analysis revealed a greater relevance of galanin system genes in highly stressed subjects compared with subjects with moderate or low life stress. Using the same method, the effect of the galanin system genes was stronger than the effect of the well-studied 5-HTTLPR polymorphism in the serotonin transporter gene (SLC6A4). Conventional multivariate analysis using general linear models demonstrated that interaction of galanin system genes with life stressors explained more variance (1.7%, P = 0.005) than the life stress-only model. This effect replicated in independent analysis of the Manchester and Budapest subpopulations, and in males and females. The results suggest that the galanin pathway plays an important role in the pathogenesis of depression in humans by increasing the vulnerability to early and recent psychosocial stress. Correcting abnormal galanin function in depression could prove to be a novel target for drug development. The findings further emphasize the importance of modeling environmental interaction in finding new genes for depression.
    Proceedings of the National Academy of Sciences 03/2014; 111(16). DOI:10.1073/pnas.1403649111 · 9.81 Impact Factor
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    ABSTRACT: Proneness to self-blaming moral emotions such as shame and guilt is increased in major depressive disorder (MDD), and may play an important role in vulnerability even after symptoms have subsided. Social psychologists have argued that shame-proneness is relevant for depression vulnerability and is distinct from guilt. Shame depends on the imagined critical perception of others, whereas guilt results from one's own judgement. The neuroanatomy of shame in MDD is unknown. Using fMRI, we compared 21 participants with MDD remitted from symptoms with no current co-morbid axis-I disorders, and 18 control participants with no personal or family history of MDD. The MDD group exhibited higher activation of the right amygdala and posterior insula for shame relative to guilt (SPM8). This neural difference was observed despite equal levels of rated negative emotional valence and frequencies of induced shame and guilt experience across groups. These same results were found in the medication-free MDD subgroup (N = 15). Increased amygdala and posterior insula activations, known to be related to sensory perception of emotional stimuli, distinguish shame from guilt responses in remitted MDD. People with MDD thus exhibit changes in the neural response to shame after symptoms have subsided. This supports the hypothesis that shame and guilt play at least partly distinct roles in vulnerability to MDD. Shame-induction may be a more sensitive probe of residual amygdala hypersensitivity in MDD compared with facial emotion-evoked responses previously found to normalize on remission.
    PLoS ONE 01/2014; 9(1):e86900. DOI:10.1371/journal.pone.0086900 · 3.53 Impact Factor
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    ABSTRACT: Background Major depressive disorder (MDD) is associated with functional abnormalities in fronto-meso-limbic networks contributing to decision-making, affective and reward processing impairments. Such functional disturbances may underlie a tendency for enhanced altruism driven by empathy-based guilt observed in some patients. However, despite the relevance of altruistic decisions to understanding vulnerability, as well as everyday psychosocial functioning, in MDD, their functional neuroanatomy is unknown. Methods Using a charitable donations experiment with fMRI, we compared 14 medication-free participants with fully remitted MDD and 15 demographically-matched control participants without MDD. Results Compared with the control group, the remitted MDD group exhibited enhanced BOLD response in a septal/subgenual cingulate cortex (sgACC) region for charitable donation relative to receiving simple rewards and higher striatum activation for both charitable donation and simple reward relative to a low level baseline. The groups did not differ in demographics, frequency of donations or response times, demonstrating only a difference in neural architecture. Conclusions We showed that altruistic decisions probe residual sgACC hypersensitivity in MDD even after symptoms are fully remitted. The sgACC has previously been shown to be associated with guilt which promotes altruistic decisions. In contrast, the striatum showed common activation to both simple and altruistic rewards and could be involved in the so-called “warm glow” of donation. Enhanced neural response in the depression group, in areas previously linked to altruistic decisions, supports the hypothesis of a possible association between hyper-altruism and depression vulnerability, as shown by recent epidemiological studies.
    01/2014; 4:701–710. DOI:10.1016/j.nicl.2014.04.010
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    ABSTRACT: The non-competitive N-methyl-D-aspartate receptor antagonist ketamine leads to transient psychosis-like symptoms and impairments in oculomotor performance in healthy volunteers. This study examined whether the adverse effects of ketamine on oculomotor performance can be reversed by the atypical antipsychotic risperidone. In this randomized double-blind, placebo-controlled study, 72 healthy participants performed smooth pursuit eye movements (SPEM), prosaccades (PS) and antisaccades (AS) while being randomly assigned to one of four drug groups (intravenous 100 ng ml(-1) ketamine, 2 mg oral risperidone, 100 ng ml(-1) ketamine plus 2 mg oral risperidone, placebo). Drug administration did not lead to harmful adverse events. Ketamine increased saccadic frequency and decreased velocity gain of SPEM (all P<0.01) but had no significant effects on PS or AS (all P0.07). An effect of risperidone was observed for amplitude gain and peak velocity of PS and AS, indicating hypometric gain and slower velocities compared with placebo (both P0.04). No ketamine by risperidone interactions were found (all P0.26). The results confirm that the administration of ketamine produces oculomotor performance deficits similar in part to those seen in schizophrenia. The atypical antipsychotic risperidone did not reverse ketamine-induced deteriorations. These findings do not support the cognitive enhancing potential of risperidone on oculomotor biomarkers in this model system of schizophrenia and point towards the importance of developing alternative performance-enhancing compounds to optimise pharmacological treatment of schizophrenia.
    Translational Psychiatry 12/2013; 3(12):e334. DOI:10.1038/tp.2013.109 · 4.36 Impact Factor
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    ABSTRACT: Major depressive disorder (MDD) is associated with abnormalities in financial reward processing. Previous research suggests that patients with MDD show reduced sensitivity to frequency of financial rewards. However, there is a lack of conclusive evidence from studies investigating the evaluation of financial rewards over time, an important aspect of reward processing that influences the way people plan long-term investments. Beck's cognitive model posits that patients with MDD hold a negative view of the future that may influence the amount of resources patients are willing to invest into their future selves. We administered a delay discounting task to 82 participants: 29 healthy controls, 29 unmedicated participants with fully remitted MDD (rMDD) and 24 participants with current MDD (11 on medication). Patients with current MDD, relative to remitted patients and healthy subjects, discounted large-sized future rewards at a significantly higher rate and were insensitive to changes in reward size from medium to large. There was a main effect of clinical group on discounting rates for large-sized rewards, and discounting rates for large-sized rewards correlated with severity of depressive symptoms, particularly hopelessness. Higher discounting of delayed rewards in MDD seems to be state dependent and may be a reflection of depressive symptoms, specifically hopelessness. Discounting distant rewards at a higher rate means that patients are more likely to choose immediate financial options. Such impairments related to long-term investment planning may be important for understanding value-based decision making in MDD, and contribute to ongoing functional impairment.
    Psychological Medicine 11/2013; 44(9):1-10. DOI:10.1017/S0033291713002584 · 5.43 Impact Factor
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    ABSTRACT: The importance of differentiating between social concepts when appraising actions (e.g., understanding behavior as critical vs. fault-finding) and its contribution to vulnerability to major depressive disorder (MDD) is unknown. We predicted poor integration of differentiated conceptual knowledge when people with MDD appraise their social actions, contributing to their tendency to grossly overgeneralize self-blame (e.g., "I am unlikable rather than critical"). To test this hypothesis, we used a neuropsychological test measuring social conceptual differentiation and its relationship with emotional biases in a remitted MDD and a control group. During fMRI, guilt- and indignation-evoking sentences were presented. As predicted, conceptual overgeneralization was associated with increased emotional intensity when appraising social actions. Interdependence of conceptual overgeneralization and negative emotional biases was stronger in MDD (reproducible in the subgroup without medication) and was associated with overgeneralized self-blame. This high conceptual-emotional interdependence was associated with functional disconnection between the right superior anterior temporal lobe (ATL) and right dorsolateral prefrontal cortex (PFC) as well as a septal region across groups when experiencing guilt (SPM8). Strong coupling of conceptual information (ATL) with information about the context of actions and emotions (frontal-subcortical regions) is thus associated with appraisal being less dependent on conceptual overgeneralization, thereby protecting against excessive self-blame.
    Social neuroscience 07/2013; 8(5). DOI:10.1080/17470919.2013.810171 · 2.87 Impact Factor
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    ABSTRACT: RATIONALE: The increasing demand to develop more efficient compounds to treat cognitive impairments in schizophrenia has led to the development of experimental model systems. One such model system combines the study of surrogate populations expressing high levels of schizotypy with oculomotor biomarkers. OBJECTIVES: We aimed (1) to replicate oculomotor deficits in a psychometric schizotypy sample and (2) to investigate whether the expected deficits can be remedied by compounds shown to ameliorate impairments in schizophrenia. METHODS: In this randomized double-blind, placebo-controlled study 233 healthy participants performed prosaccade (PS), antisaccade (AS) and smooth pursuit eye movement (SPEM) tasks after being randomly assigned to one of four drug groups (nicotine, risperidone, amisulpride, placebo). Participants were classified into medium- and high-schizotypy groups based on their scores on the Schizotypal Personality Questionnaire (SPQ, Raine (Schizophr Bull 17:555-564, 1991)). RESULTS: AS error rate showed a main effect of Drug (p < 0.01), with nicotine improving performance, and a Drug by Schizotypy interaction (p = 0.04), indicating higher error rates in medium schizotypes (p = 0.01) but not high schizotypes under risperidone compared to placebo. High schizotypes had higher error rates than medium schizotypes under placebo (p = 0.03). There was a main effect of Drug for saccadic peak velocity and SPEM velocity gain (both p ≤ 0.01) indicating impaired performance with risperidone. CONCLUSIONS: We replicate the observation of AS impairments in high schizotypy under placebo and show that nicotine enhances performance irrespective of group status. Caution should be exerted in applying this model as no beneficial effects of antipsychotics were seen in high schizotypes.
    Psychopharmacology 02/2013; 227(2). DOI:10.1007/s00213-013-2973-4 · 3.99 Impact Factor
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    ABSTRACT: The catechol-o-methyltransferase (COMT) gene has been extensively investigated in depression with somewhat contradictory results but the role of impulsivity, as a possible intermediate phenotype in this disorder, has not been considered yet. In our study, four tagging SNPs in the COMT gene (rs933271, rs740603, rs4680, rs4646316) were genotyped in two independent population cohorts: Manchester (n = 1267) and Budapest (n = 942). First, we investigated the association between COMT genotypes, impulsivity, neuroticism and depression using haplotype trend regression, and constructed a model using structural equation modeling to investigate the interaction between these factors. Secondly, we tested the effect of executive function on this model in a smaller interviewed sample (n = 207). Our results demonstrated that COMT haplotypes were significantly associated with impulsivity in the combined cohort, showing the same direction of effects in both populations. The COMT effect on depressive symptoms (in subjects without history of depression) and on executive function (interviewed sample) showed the opposite pattern to impulsivity. Structural equation models demonstrated that COMT and impulsivity acted, both together (through neuroticism) and independently, to increase the risk of depression. In addition, better executive function also operated as a risk factor for depression, possibly though reduced ability to flexibly disengage negative emotions. In conclusion, variations in the COMT gene exert complex effects on susceptibility to depression involving various intermediate phenotypes, such as impulsivity and executive function. These findings emphasise that modeling of disease pathways at phenotypic level are valuable for identifying genetic risk factors. © 2012 Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part B Neuropsychiatric Genetics 12/2012; 159B(8). DOI:10.1002/ajmg.b.32098 · 3.27 Impact Factor
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    ABSTRACT: Reduced hippocampal volume has been reported in depression and may be involved in the aetiology of depressive symptoms and vulnerability to depressive relapse. Neuroplasticity following antidepressant drug treatment in the hippocampus has been demonstrated in animal models but adaptive changes after such treatment have not been shown in humans. In this study, we determined whether grey matter loss in the hippocampus in depression (1) is present in medication-free depressed (2) changes in response to antidepressant treatment and (3) is present as a stable trait in medication-free remitted patients. Sixty-four medication-free unipolar depressed patients: 39 currently depressed and 25 in remission, and 66 healthy controls (HC) underwent structural magnetic resonance imaging in a cross-sectional and longitudinal design. Thirty-two currently depressed participants were then treated with the antidepressant citalopram for 8 weeks. Adherence to treatment was evaluated by measuring plasma citalopram concentration. We measured regional variation in grey matter concentration by using voxel-based morphometry-Diffeomorphic Anatomical Registration Through Exponentiated Lie algebra. Patients with current depression had bilaterally reduced grey matter in the hippocampus compared with HC and untreated patients in stable remission with the latter groups not differing. An increase in grey matter was observed in the hippocampus following treatment with citalopram in currently depressed patients. Grey matter reduction in the hippocampus appears specific to the depressed state and is a potential biomarker for a depressive episode.Molecular Psychiatry advance online publication, 6 November 2012; doi:10.1038/mp.2012.150.
    Molecular Psychiatry 11/2012; DOI:10.1038/mp.2012.150 · 15.15 Impact Factor
  • European Neuropsychopharmacology 10/2012; 22:S135. DOI:10.1016/S0924-977X(12)70171-2 · 5.40 Impact Factor
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    ABSTRACT: AIMS: Pharmacological-challenge magnetic resonance imaging (phMRI) is powerful new tool enabling researchers to map the central effects of neuroactive drugs in vivo. To employ this technique pre-clinically, head movements and the stress of restraint are usually reduced by maintaining animals under general anaesthesia. However, interactions between the drug of interest and the anaesthetic employed may potentially confound data interpretation. NMDA receptor (NMDAR) antagonists used widely to mimic schizophrenia have recently been shown to interact with the anaesthetic halothane. It may be the case that neural and cerebrovascular responses to NMDAR antagonists are dependent on the types of anaesthetic used. METHODOLOGY: We compared the phMRI response to NMDAR antagonist ketamine in rats maintained under α-chloralose to those under isoflurane anaesthesia. A randomized placebo/vehicle controlled design was used in each of the anaesthetic groups. RESULTS: Changes in the anaesthetic agent resulted in two very different profiles of activity. In the case of α-chloralose, positive activations in cortical and sub-cortical structures reflected a response which was similar to patterns seen in healthy human volunteers and metabolic maps of conscious rats. However, the use of isoflurane completely reversed such effects, causing widespread deactivations in the cortex and hippocampus. CONCLUSION: This study provides initial evidence for a drug-anesthetic interaction between ketamine and isoflurane that is very different from responses to α-chloralose-ketamine.
    09/2012; 2(3):373-385.
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    ABSTRACT: Background: One widespread view holds that vulnerability to major depressive disorder (MDD) is linked to overall increases in negative emotionality. In contrast, cognitive attribution theories emphasize the importance of blaming oneself rather than others for negative events. Thus far, the contrasting predictions of these models have not been directly compared. Following the attributional perspective, we tested the hypothesis that people with remitted MDD show no overall bias towards negative emotions, but a selective bias towards self-blaming emotions relative to those emotions associated with blaming others. Sampling and Methods: We compared a remitted MDD and a control group on a novel experimental test that allowed us to directly compare proneness to specific emotions associated with different types of self-blame (guilt, shame, self-contempt/disgust) and blame of others (other-indignation/anger, other-contempt/disgust) whilst controlling for negative valence and medication status, and excluding comorbidity. Results: In agreement with our hypothesis, individuals with remitted MDD exhibited an increased self-contempt bias (difference between contempt/disgust towards self and others) but no increased proneness to any other negative emotion or overall increases in perceived negative valence of stimuli. Moreover, the remitted MDD group exhibited reduced contempt/disgust towards others. Conclusions: Our results corroborate the prediction that vulnerability to MDD is associated with an imbalance of specific self- and other-blaming emotions rather than a general increase in negative emotions. Based on the composition of our sample, we speculate that self-contempt bias may be particularly characteristic of melancholic MDD subtypes and could be useful for stratification of depression in the future.
    Psychopathology 08/2012; 46(1). DOI:10.1159/000338632 · 1.56 Impact Factor
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    ABSTRACT: Increased amygdala response to negative emotions seen in functional MRI (fMRI) has been proposed as a biomarker for negative emotion processing bias underlying depressive symptoms and vulnerability to depressive relapse that are normalized by antidepressant drug treatment. The purpose of this study was to determine whether abnormal amygdala responses to face emotions in depression are related to specific emotions or change in response to antidepressant treatment and whether they are present as a stable trait in medication-free patients in remission. Sixty-two medication-free unipolar depressed patients (38 were currently depressed, and 24 were in remission) and 54 healthy comparison subjects underwent an indirect face-emotion processing task during fMRI. Thirty-two currently depressed patients were treated with the antidepressant citalopram for 8 weeks. Adherence to treatment was evaluated by measuring citalopram plasma concentrations. Patients with current depression had increased bilateral amygdala responses specific to sad faces relative to healthy comparison subjects and nonmedicated patients in stable remission. Treatment with citalopram abolished the abnormal amygdala responses to sad faces in currently depressed patients but did not alter responses to fearful faces. Aberrant amygdala activation in response to sad facial emotions is specific to the depressed state and is a potential biomarker for a negative affective bias during a depressive episode.
    American Journal of Psychiatry 08/2012; 169(8):841-50. DOI:10.1176/appi.ajp.2012.11121774 · 13.56 Impact Factor
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    ABSTRACT: Vulnerability to relapse persists after remission of an acute episode of major depressive disorder. This has been attributed to abnormal biases in the processing of emotional stimuli in limbic circuits. However, neuroimaging studies have not so far revealed consistent evidence of abnormal responses to emotional stimuli in limbic structures, such as the amygdala, in remitted depression. This suggests the problem might lie in the integrated functioning of emotion processing circuits. We recruited 22 unmedicated patients in remission from major depressive disorder (rMDD) and 21 age-matched healthy control subjects. Functional magnetic resonance imaging was performed during a face emotion processing task. Dynamic causal modeling was used with Bayesian model selection to determine the most likely brain networks and valence-specific modulation of connectivity in healthy control subjects and rMDD. In healthy volunteers, sad faces modulated bi-directional connections between amygdala and orbitofrontal cortex and between fusiform gyrus and orbitofrontal cortex. Happy faces modulated unidirectional connections from fusiform gyrus to orbitofrontal cortex. In rMDD, the opposite pattern was observed, with evidence of happy faces modulating bidirectional frontotemporal connections and sad faces modulating unidirectional fusiform-orbitofrontal connections. Participants with rMDD have abnormal modulation of frontotemporal effective connectivity in response to happy and sad face emotions, despite normal activations within each region. Specifically, processing of mood incongruent happy information was associated with a more richly modulated frontotemporal brain network, whereas mood congruent sad information was associated with less network modulation. This supports a hypothesis of dysfunction within cortico-limbic connections in individuals vulnerable to depression.
    Biological psychiatry 06/2012; 72(7):604-11. DOI:10.1016/j.biopsych.2012.04.031 · 9.47 Impact Factor

Publication Stats

8k Citations
1,292.02 Total Impact Points

Institutions

  • 1985–2014
    • The University of Manchester
      • Neuroscience & Psychiatry Unit
      Manchester, England, United Kingdom
    • MRC Clinical Sciences Centre
      London Borough of Harrow, England, United Kingdom
  • 2007–2008
    • University of Melbourne
      • Department of Psychiatry
      Melbourne, Victoria, Australia
  • 2001–2005
    • Imperial College London
      • MRC Clinical Sciences Centre
      Londinium, England, United Kingdom
    • University of Oxford
      Oxford, England, United Kingdom
  • 1997–2003
    • University of São Paulo
      • Faculty of Medicine (FM)
      São Paulo, Estado de Sao Paulo, Brazil
  • 2002
    • Lancaster University
      • Department of Psychology
      Lancaster, ENG, United Kingdom
    • Dalhousie University
      Halifax, Nova Scotia, Canada
  • 1999
    • University of Cambridge
      Cambridge, England, United Kingdom
  • 1996
    • Advance MRI
      Frisco, Texas, United States
  • 1993
    • University of Bristol
      Bristol, England, United Kingdom
  • 1990
    • University Hospital Of South Manchester NHS Foundation Trust
      Manchester, England, United Kingdom
  • 1977–1981
    • MRC National Institute for Medical Research
      • Division of Neurophysiology
      London, ENG, United Kingdom
  • 1980
    • The School of Pharmacy
      • Pharmacology
      Londinium, England, United Kingdom