Neural markers of symptomatic improvement during antidepressant therapy in severe depression: Subgenual cingulate and visual cortical responses to sad, but not happy, facial stimuli are correlated with changes in symptom score

Cardiff University, Psychological Medicine, Cardiff, UK.
Journal of Psychopharmacology (Impact Factor: 2.81). 09/2009; 23(7):775-88. DOI: 10.1177/0269881108093589
Source: PubMed

ABSTRACT Resting state activity in the ventral cingulate may be an important neural marker of symptomatic improvement in depression. The number of task related functional magnetic resonance imaging (fMRI) studies correlating blood oxygenation level dependent (BOLD) response with symptomatic improvement is limited and methodologies are still evolving. We measured BOLD responses to sad and happy facial stimuli in 12 severely depressed individuals in the early stages of antidepressant treatment (Time 1) and 12 weeks later (Time 2) using event-related fMRI. We calculated correlations between temporal changes in BOLD response and changes in symptom scores. Most subjects improved markedly by Time 2. At Time 1, depression severity correlated positively with responses to sad stimuli in the right visual cortex, subgenual cingulate, anterior temporal pole and hippocampus and correlated negatively with responses to happy stimuli in left visual cortex and right caudate. Decreases in individual effect sizes of right subgenual cingulate and right visual cortical responses to sad, but not happy, facial stimuli were correlated with decreases in symptom scores. There are contrasting cortical and subcortical responses to sad and happy stimuli in severe depression. Responses to sad stimuli show the strongest correlates of clinical improvement, particularly in the subgenual cingulate.

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    • "Significance was set at an uncorrected threshold of po0.005 with more than 100 contiguous voxels for exploratory whole brain analysis. From the results of the exploratory whole brain analysis, we found the areas in the limbiccortical network including bilateral amygdala, caudate, putamen, insular, ACC, visual cortex and DLPFC (Mayberg et al., 1999; Keedwell et al., 2009; Li et al., 2010). For the multiple comparisons correction, the significant clusters were performed by Small- Volume Correction (SVC) with an anatomically defined regional mask from WFU PickAtlas Tool ( "
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    ABSTRACT: Background Voxel-based morphometry (VBM) has demonstrated structural brain changes between patients with Major Depressive Disorder (MDD) and healthy individuals. The initial response to antidepressants is crucial to predict prognosis in the treatment of MDD. The aim of the present study was to investigate gray matter abnormalities predicting antidepressant responsiveness and the relationships between volumetric differences and clinical/cognitive traits in MDD patients. Methods Fifty MDD patients who received 8 week period antidepressant treatment and 29 healthy controls participated in this study. VBM was applied to assess structural changes between MDD groups and control group. Neuropsychological tests were conducted on all participants. Results Both treatment responsive and non-responsive patients showed a significant volume reduction of the left insular, but only non-responsive patients had decreased volume in the right superior frontal gyrus compared to healthy controls. The comparison between treatment responsive and non-responsive patient groups demonstrated a significant difference in gray matter volume in the lingual gyrus. The larger volume of lingual gryus predicted early antidepressant response, which was attributable to better performance in neuropsychological tests. Limitation This study included a small sample size and the patients received various antidepressants and benzodiazepines. Conclusion Our findings suggest that the patients who responded poorly to antidepressants were morphologically and cognitively impaired, whereas the treatment responsive patients showed less structural changes and relatively preserved cognitive functions. The lingual gyrus may be a possible candidate region to predict antidepressant responsiveness and maintained cognition in MDD.
    Journal of Affective Disorders 12/2014; 169:179–187. DOI:10.1016/j.jad.2014.08.018 · 3.71 Impact Factor
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    • "Evaluating antidepressant effects on emotion processing neurocircuitry can provide important insights into illness states, as well as potential biomarkers of response, all of which can contribute to improving selection of current therapies and development of future targeted therapeutics. A replicated outcome when employing emotional provocation techniques evaluated with fMRI in depressed states is overactivity in the subgenual cingulate, amygdala, insula, and prefrontal cortex (Anand et al., 2005; Harmer et al., 2009; Keedwell et al., 2009; Kalin et al., 1997; Sheline et al., 2001). These abnormalities are noted to normalize following successful treatment with selective Contents lists available at ScienceDirect journal homepage: "
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    ABSTRACT: Major Depressive Disorder (MDD) is a leading cause of disability globally. Currently available treatments have limited efficacy and combination strategies are frequently used. Several lines of research have demonstrated that MDD patients experience impairments in various components of affective processing, including regulation of affective states. To identify baseline and 1-week neuroimaging predictors of response to a 6-week trial of fluoxetine/olanzapine combination treatment during an affective processing task. Twenty-one MDD patients and 18 healthy controls were enrolled in the study. MDD patients were treated for 6 weeks with fluoxetine (40-60mg/day) and olanzapine (5-12.5mg/day). All participants viewed images from the International Affective Picture Rating System during a functional magnetic resonance (fMRI) scan at baseline and 1 week. There was a 57% response rate (defined as a 50% decrease in Hamilton Rating Scale for Depression-17 item) at 6 weeks. At baseline, responders had increased premotor activity while viewing negative images compared to non-responders and healthy controls. Higher baseline premotor activity was also predictive of greater percent change on the HAMD-17 and improvement in negative disposition and behavioral drive. Non-responders exhibited increased insular activity at baseline compared to responders. Higher activity in the posterior cingulate cortex was also predictive of greater percent change on the HAMD-17. Change from baseline to 1 week did not produce any significant predictive findings. Treatment with fluoxetine/olanzapine demonstrated similar biomarkers of response to monotherapeutic strategies. In particular, posterior cingulate cortex, anterior insula, and premotor cortex may show predictive differences in their response to affective images prior to treatment. Further research needs to be conducted to determine the utility of early changes in emotion circuitry in predicting antidepressant response.
    Journal of Affective Disorders 08/2013; 151(2). DOI:10.1016/j.jad.2013.06.050 · 3.71 Impact Factor
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    • "During the course of treatment, brain activity can change or " normalize " in these regions (Sheline et al. 2001; Davidson et al. 2003; Fu et al. 2004; Little et al. 2005; Keedwell et al. 2009; Frodl et al. 2011; meta-analysis— Fitzgerald et al. 2008). Thus, applying clinically effective treatments can influence brain activity in previously " dysfunctional " regions, corresponding to the clinical improvement. "
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    ABSTRACT: Most widely used antidepressant drugs affect the serotonergic and noradrenergic pathways. However, there are currently no neurobiological criteria for selecting between these targets and predicting the treatment response in individual depressed patients. The current study is aimed at differentiating brain regions known to be pathophysiologically and functionally involved in depression-related emotion processing with respect to their susceptibility to serotonergic and noradrenergic modulation. In a single-blind pseudo-randomized crossover study, 16 healthy subjects (out of 21 enrolled) were included in analysis after ingesting a single dose of citalopram (a selective serotonin-reuptake inhibitor, 40 mg), reboxetine (a selective noradrenaline-reuptake inhibitor, 8 mg), or placebo at three time points prior to functional magnetic resonance imaging (fMRI). During fMRI, subjects anticipated and subsequently viewed emotional pictures. Effects of serotonergic and noradrenergic modulation versus placebo on brain activity during the perception of negative pictures were analyzed with a repeated measures ANOVA in the whole brain and in specific regions of interest relevant to depression. Noradrenergic modulation by reboxetine increased brain activity in the thalamus, right dorsolateral prefrontal cortex and occipital regions during the perception of negative emotional stimuli. Citalopram primarily affected the ventrolateral prefrontal cortical regions. The brain regions involved in the processing of negative emotional stimuli were differentially modulated by selective noradrenergic and serotonergic drugs: thalamic activity was increased by reboxetine, whereas citalopram primarily affected ventrolateral prefrontal regions. Thus, dysfunction in these regions, which could be identified in depressed patients, may predict treatment responses to either noradrenergic or serotonergic antidepressants.
    Psychopharmacology 02/2011; 216(3):389-99. DOI:10.1007/s00213-011-2227-2 · 3.99 Impact Factor
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