Impaired reward-related learning signals in remitted unmedicated patients with recurrent depression

One of the core symptoms of major depressive disorder is anhedonia, an inability to experience pleasure. In patients with major depressive disorder, a dysfunctional reward-system may exist, with blunted temporal difference reward-related learning signals in the ventral striatum and increased temporal difference-related (dopaminergic) activation in the ventral tegmental area. Anhedonia often remains as residual symptom during remission; however, it remains largely unknown whether the abovementioned reward systems are still dysfunctional when patients are in remission. We used a Pavlovian classical conditioning functional MRI task to explore the relationship between anhedonia and the temporal difference-related response of the ventral tegmental area and ventral striatum in medication-free remitted recurrent depression patients (n = 36) versus healthy control subjects (n = 27). Computational modelling was used to obtain the expected temporal difference errors during this task. Patients, compared to healthy controls, showed significantly increased temporal difference reward learning activation in the ventral tegmental area (PFWE,SVC = 0.028). No differences were observed between groups for ventral striatum activity. A group × anhedonia interaction [t(57) = -2.29, P = 0.026] indicated that in patients, higher anhedonia was associated with lower temporal difference activation in the ventral tegmental area, while in healthy controls higher anhedonia was associated with higher ventral tegmental area activation. These findings suggest impaired reward-related learning signals in the ventral tegmental area during remission in patients with depression. This merits further investigation to identify impaired reward-related learning as an endophenotype for recurrent depression. Moreover, the inverse association between reinforcement learning and anhedonia in patients implies an additional disturbing influence of anhedonia on reward-related learning or vice versa, suggesting that the level of anhedonia should be considered in behavioural treatments

Decreased functional connectivity of the insula within the salience network as an indicator for prospective insufficient response to antidepressants

Insufficient response to treatment is the main cause of prolonged suffering from major depressive disorder (MDD). Early identification of insufficient response could result in faster and more targeted treatment strategies to reduce suffering. We therefore explored whether baseline alterations within and between resting state functional connectivity networks could serve as markers of insufficient response to antidepressant treatment in two years of follow-up. We selected MDD patients (N = 17) from the NEtherlands Study of Depression and Anxiety (NESDA), who received ≥ two antidepressants, indicative for insufficient response, during the two year follow-up, a group of MDD patients who received only one antidepressant (N = 32) and a healthy control group (N = 19) matched on clinical characteristics and demographics. An independent component analysis (ICA) of baseline resting-state scans was conducted after which functional connectivity within the components was compared between groups. We observed lower connectivity of the right insula within the salience network in the group with ≥ two antidepressants compared to the group with one antidepressant. No difference in connectivity was found between the patient groups and healthy control group. Given the suggested role of the right insula in switching between task-positive mode (activation during attention-demanding tasks) and task-negative mode (activation during the absence of any task), we explored whether right insula activation differed during switching between these two modes. We observed that in the ≥2 antidepressant group, the right insula was less active compared to the group with one antidepressant, when switching from task-positive to task-negative mode than the other way around. These findings imply that lower right insula connectivity within the salience network may serve as an indicator for prospective insufficient response to antidepressants. This result, supplemented by the diminished insula activation when switching between task and rest related networks, could indicate an underlying mechanism that, if not sufficiently targeted by current antidepressants, could lead to insufficient response. When replicated, these findings may contribute to the identification of biomarkers for early detection of insufficient response

Vulnerability for new episodes in recurrent major depressive disorder:protocol for the longitudinal DELTA-neuroimaging cohort study

Introduction Major depressive disorder (MDD) is widely prevalent and severely disabling, mainly due to its recurrent nature. A better understanding of the mechanisms underlying MDD-recurrence may help to identify high-risk patients and to improve the preventive treatment they need. MDD-recurrence has been considered from various levels of perspective including symptomatology, affective neuropsychology, brain circuitry and endocrinology/metabolism. However, MDD-recurrence understanding is limited, because these perspectives have been studied mainly in isolation, cross-sectionally in depressed patients. Therefore, we aim at improving MDD-recurrence understanding by studying these four selected perspectives in combination and prospectively during remission.Methods and analysis In a cohort design, we will include 60 remitted, unipolar, unmedicated, recurrent MDD-participants (35-65years) with 2 MDD-episodes. At baseline, we will compare the MDD-participants with 40 matched controls. Subsequently, we will follow-up the MDD-participants for 2.5years while monitoring recurrences. We will invite participants with a recurrence to repeat baseline measurements, together with matched remitted MDD-participants. Measurements include questionnaires, sad mood-induction, lifestyle/diet, 3T structural (T1-weighted and diffusion tensor imaging) and blood-oxygen-level-dependent functional MRI (fMRI) and MR-spectroscopy. fMRI focusses on resting state, reward/aversive-related learning and emotion regulation. With affective neuropsychological tasks we will test emotional processing. Moreover, we will assess endocrinology (salivary hypothalamic-pituitary-adrenal-axis cortisol and dehydroepiandrosterone-sulfate) and metabolism (metabolomics including polyunsaturated fatty acids), and store blood for, for example, inflammation analyses, genomics and proteomics. Finally, we will perform repeated momentary daily assessments using experience sampling methods at baseline. We will integrate measures to test: (1) differences between MDD-participants and controls; (2) associations of baseline measures with retro/prospective recurrence-rates; and (3) repeated measures changes during follow-up recurrence. This data set will allow us to study different predictors of recurrence in combination.Ethics and dissemination The local ethics committee approved this study (AMC-METC-Nr.:11/050). We will submit results for publication in peer-reviewed journals and presentation at (inter)national scientific meetings.Trial registration number NTR3768.</p

Decreased functional connectivity of the insula within the salience network as an indicator for prospective insufficient response to antidepressants

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Associations between daily affective instability and connectomics in functional subnetworks in remitted patients with recurrent major depressive disorder

Item does not contain fulltextRemitted patients with major depressive disorder (rMDD) often report more fluctuations in mood as residual symptomatology. It is unclear how this affective instability is associated with information processing related to the default mode (DMS), salience/reward (SRS) and fronto-parietal (FPS) subnetworks in rMDD patients at high risk of recurrence (rrMDD). Sixty-two unipolar, drug-free rrMDD patients ([ges]2 MDD-episodes) and 41 HC (HC) were recruited. We used Experience Sampling Methodology (ESM) to monitor mood/cognitions (10 times a day for 6 days) and calculated affective instability using the mean adjusted absolute successive difference. Subsequently, we collected resting-state functional Magnetic Resonance Imaging data and performed graph theory to obtain network metrics of integration within (local efficiency) the DMS, SRS and FPS, and between (participation coefficient) these subnetworks and others. In rrMDD patients compared to HC, we found that affective instability was increased in most negative mood/cognition variables and that the DMS had less connections with other subnetworks. Furthermore, we found that rrMDD patients, who showed more instability in feeling down and irritated, had less connections between the SRS and other subnetworks and higher local efficiency coefficients in the FPS, respectively. In conclusion, rrMDD patients, compared to HC, are less stable in their negative mood and these dynamics are related to differences in information processing within and between specific functional subnetworks. These results are a first step to gain a better understanding of how mood fluctuations in real-life are represented in the brain and provide insights in the vulnerability profile of MDD.10 p

Vulnerability for new episodes in recurrent major depressive disorder: protocol for the longitudinal DELTA-neuroimaging cohort study

Major depressive disorder (MDD) is widely prevalent and severely disabling, mainly due to its recurrent nature. A better understanding of the mechanisms underlying MDD-recurrence may help to identify high-risk patients and to improve the preventive treatment they need. MDD-recurrence has been considered from various levels of perspective including symptomatology, affective neuropsychology, brain circuitry and endocrinology/metabolism. However, MDD-recurrence understanding is limited, because these perspectives have been studied mainly in isolation, cross-sectionally in depressed patients. Therefore, we aim at improving MDD-recurrence understanding by studying these four selected perspectives in combination and prospectively during remission.In a cohort design, we will include 60 remitted, unipolar, unmedicated, recurrent MDD-participants (35-65 years) with ≥ 2 MDD-episodes. At baseline, we will compare the MDD-participants with 40 matched controls. Subsequently, we will follow-up the MDD-participants for 2.5 years while monitoring recurrences. We will invite participants with a recurrence to repeat baseline measurements, together with matched remitted MDD-participants. Measurements include questionnaires, sad mood-induction, lifestyle/diet, 3 T structural (T1-weighted and diffusion tensor imaging) and blood-oxygen-level-dependent functional MRI (fMRI) and MR-spectroscopy. fMRI focusses on resting state, reward/aversive-related learning and emotion regulation. With affective neuropsychological tasks we will test emotional processing. Moreover, we will assess endocrinology (salivary hypothalamic-pituitary-adrenal-axis cortisol and dehydroepiandrosterone-sulfate) and metabolism (metabolomics including polyunsaturated fatty acids), and store blood for, for example, inflammation analyses, genomics and proteomics. Finally, we will perform repeated momentary daily assessments using experience sampling methods at baseline. We will integrate measures to test: (1) differences between MDD-participants and controls; (2) associations of baseline measures with retro/prospective recurrence-rates; and (3) repeated measures changes during follow-up recurrence. This data set will allow us to study different predictors of recurrence in combination.The local ethics committee approved this study (AMC-METC-Nr.:11/050). We will submit results for publication in peer-reviewed journals and presentation at (inter)national scientific meetings.NTR3768

Validity of the Maudsley Staging Method in Predicting Treatment-Resistant Depression Outcome Using the Netherlands Study of Depression and Anxiety

OBJECTIVE: We investigated if the degree of treatment resistance of depression, as measured by the Maudsley Staging Method (MSM), is predictive of a worse depression outcome by using a large naturalistic cohort of depressed patients. METHODS: 643 subjects from the general population, primary care, and secondary care who suffered from current depressive disorder were included from the Netherlands Study of Depression and Anxiety baseline assessment. The diagnostic criterion was major depressive disorder (MDD) in the last month, based on the Composite Interview Diagnostic Instrument (CIDI), or a CIDI diagnosis of MDD in the past 6 months with an Inventory of Depressive Symptomatology Self-Report score > 24 at baseline. In these subjects, composite scores of the MSM, based on duration, severity, and treatment history of current episode, were determined retrospectively. We then determined if the MSM score prospectively predicted the 2-year course of depression after baseline. The primary outcomes were percentage of follow-up time spent in a depressive episode and being "mostly depressed" (≥ 50% of the follow-up) between baseline and 2-year follow-up. RESULTS: The MSM predicted "percentage of follow-up time with depression" (P < .001) and was associated with being "mostly depressed" (OR = 1.40; 95% CI, 1.23-1.60; P < .001). These effects were not modified by having received treatment. CONCLUSIONS: The current study shows that the MSM is a promising tool to predict worse depression outcomes in depressed patients. In this study that adds to previous work, we show the applicability of MSM in a wider range of primary and secondary care patients with depression

Vulnerability for new episodes in recurrent major depressive disorder : Protocol for the longitudinal DELTA-neuroimaging cohort study

Abstract Introduction Major depressive disorder (MDD) is widely prevalent and severely disabling, mainly due to its recurrent nature. A better understanding of the mechanisms underlying MDD-recurrence may help to identify high-risk patients and to improve the preventive treatment they need. MDD-recurrence has been considered from various levels of perspective including symptomatology, affective neuropsychology, brain circuitry and endocrinology/metabolism. However, MDD-recurrence understanding is limited, because these perspectives have been studied mainly in isolation, cross-sectionally in depressed patients. Therefore, we aim at improving MDD-recurrence understanding by studying these four selected perspectives in combination and prospectively during remission. Methods and analysis In a cohort design, we will include 60 remitted, unipolar, unmedicated, recurrent MDD-participants (35–65 years) with ≥2 MDD-episodes. At baseline, we will compare the MDD-participants with 40 matched controls. Subsequently, we will follow-up the MDD-participants for 2.5 years while monitoring recurrences. We will invite participants with a recurrence to repeat baseline measurements, together with matched remitted MDD-participants. Measurements include questionnaires, sad mood-induction, lifestyle/diet, 3 T structural (T1-weighted and diffusion tensor imaging) and blood-oxygen-level-dependent functional MRI (fMRI) and MR-spectroscopy. fMRI focusses on resting state, reward/aversive-related learning and emotion regulation. With affective neuropsychological tasks we will test emotional processing. Moreover, we will assess endocrinology (salivary hypothalamic-pituitary-adrenal-axis cortisol and dehydroepiandrosterone-sulfate) and metabolism (metabolomics including polyunsaturated fatty acids), and store blood for, for example, inflammation analyses, genomics and proteomics. Finally, we will perform repeated momentary daily assessments using experience sampling methods at baseline. We will integrate measures to test: (1) differences between MDD-participants and controls; (2) associations of baseline measures with retro/prospective recurrence-rates; and (3) repeated measures changes during follow-up recurrence. This data set will allow us to study different predictors of recurrence in combination. Ethics and dissemination The local ethics committee approved this study (AMC-METC-Nr.:11/050). We will submit results for publication in peer-reviewed journals and presentation at (inter)national scientific meetings. Trial registration number NTR3768

Associations Between Daily Affective Instability and Connectomics in Functional Subnetworks in Remitted Patients with Recurrent Major Depressive Disorder

Remitted patients with major depressive disorder (rMDD) often report more fluctuations in mood as residual symptomatology. It is unclear how this affective instability is associated with information processing related to the default mode (DMS), salience/reward (SRS), and frontoparietal (FPS) subnetworks in rMDD patients at high risk of recurrence (rrMDD). Sixty-two unipolar, drug-free rrMDD patients (>= 2 MDD episodes) and 41 healthy controls (HCs) were recruited. We used experience sampling methodology to monitor mood/cognitions (10 times a day for 6 days) and calculated affective instability using the mean adjusted absolute successive difference. Subsequently, we collected resting-state functional magnetic resonance imaging data and performed graph theory to obtain network metrics of integration within (local efficiency) the DMS, SRS, and FPS, and between (participation coefficient) these subnetworks and others. In rrMDD patients compared with HCs, we found that affective instability was increased in most negative mood/cognition variables and that the DMS had less connections with other subnetworks. Furthermore, we found that rrMDD patients, who showed more instability in feeling down and irritated, had less connections between the SRS and other subnetworks and higher local efficiency coefficients in the FPS, respectively. In conclusion, rrMDD patients, compared with HCs, are less stable in their negative mood and these dynamics are related to differences in information processing within-and between-specific functional subnetworks. These results are a first step to gain a better understanding of how mood fluctuations in real life are represented in the brain and provide insights into the vulnerability profile of MDD