Henricus G. Ruhé

Neural correlates of dysfunctional emotion regulation in major depressive disorder. A systematic review of neuroimaging studies

Abnormal emotion processing is a core feature of major depressive disorder (MDD). Since the emergence of functional neuroimaging techniques, many studies have been conducted in MDD subjects to elucidate the underlying abnormalities in the neural systems involved in emotion regulation. In this systematic review, we discuss this research in the context of the neural model of emotion regulation previously described by Phillips et al. (2008). This model differentiates between automatic and voluntary emotion regulation subprocesses. Automatic regulation subprocesses were shown to involve predominantly medial prefrontal cortical structures, in addition to the hippocampus and parahippocampus, while voluntary regulation processes additionally recruited lateral prefrontal cortical regions. In conclusion, although the available data is limited, findings suggest that MDD subjects demonstrate abnormally reduced activity in lateral prefrontal cortices during explicit voluntary control of emotional experience. During early, automatic stages of emotion regulation, on the other hand, MDD subjects appear to achieve successful emotion regulation by recruiting additional lateral prefrontal neural regions, that may be mediated by medial prefrontal, especially rostral/dorsal anterior cingulate gyrus (ACG) functioning. Dysfunctional automatic regulation may impair successful voluntary emotion regulation, and may present a target for novel therapeutic approaches in MDD.

Staging methods for treatment resistant depression. A systematic review

BACKGROUND Treatment resistant depressant (TRD) is classified in different staging models, but these are not used routinely. We aimed to identify staging models for TRD and compare them regarding predictive utility and reliability. METHODS Systematic review of Pubmed, Embase and PsycINFO (1985-January 2010) without language limits, plus articles identified from reference lists of previous reviews. We excluded articles focusing on TRD treatment. We qualitatively summarized characteristics of the identified staging models, describing strengths and limitations for each model. If available, we reported results of validation studies. RESULTS From 950 retrieved articles five staging models were found; the Antidepressant Treatment History Form, Thase and Rush Model, European Staging Model, Massachusetts General Hospital Staging model and the Maudsley Staging Model (MSM). Six studies investigated the predictive utility (of four models). We observed an evolution from single antidepressant adequacy ratings, towards a multidimensional and more continuous scored staging model which also introduced TRD characteristics (severity and duration). The operationalization criteria improved; the scoring of different treatment strategies (between/within class switching and augmentation/combination) changed according to the existing evidence. Over time, efforts to validate models improved. The predictive utility was assessed best for the MSM. LIMITATIONS Few staging models existed; their reliability was hardly assessed. CONCLUSIONS Despite validation of the MSM, further investigation of the reliability and predictive utility of TRD staging models and additional disease characteristics is required. Correct staging of TRD might improve generalizability of results from clinical studies and improve delivery of care to TRD patients. We propose methods to validate staging models in TRD.

Meta-analysis and meta-regression of omega-3 polyunsaturated fatty acid supplementation for major depressive disorder.

Omega-3 polyunsaturated fatty acid (PUFA) supplementation has been proposed as (adjuvant) treatment for major depressive disorder (MDD). In the present meta-analysis, we pooled randomized placebo-controlled trials assessing the effects of omega-3 PUFA supplementation on depressive symptoms in MDD. Moreover, we performed meta-regression to test whether supplementation effects depended on eicosapentaenoic acid (EPA) or docosahexaenoic acid dose, their ratio, study duration, participants’ age, percentage antidepressant users, baseline MDD symptom severity, publication year and study quality. To limit heterogeneity, we only included studies in adult patients with MDD assessed using standardized clinical interviews, and excluded studies that specifically studied perinatal/perimenopausal or comorbid MDD. Our PubMED/EMBASE search resulted in 1955 articles, from which we included 13 studies providing 1233 participants. After taking potential publication bias into account, meta-analysis showed an overall beneficial effect of omega-3 PUFAs on depressive symptoms in MDD (standardized mean difference=0.398 (0.114–0.682), P=0.006, random-effects model). As an explanation for significant heterogeneity (I2=73.36, P<0.001), meta-regression showed that higher EPA dose (β=0.00037 (0.00009–0.00065), P=0.009), higher percentage antidepressant users (β=0.0058 (0.00017–0.01144), P=0.044) and earlier publication year (β=−0.0735 (−0.143 to 0.004), P=0.04) were significantly associated with better outcome for PUFA supplementation. Additional sensitivity analyses were performed. In conclusion, present meta-analysis suggested a beneficial overall effect of omega-3 PUFA supplementation in MDD patients, especially for higher doses of EPA and in participants taking antidepressants. Future precision medicine trials should establish whether possible interactions between EPA and antidepressants could provide targets to improve antidepressant response and its prediction. Furthermore, potential long-term biochemical side effects of high-dosed add-on EPA supplementation should be carefully monitored.

Effects of oxidative stress on fatty acid- and one-carbon-metabolism in psychiatric and cardiovascular disease comorbidity

Cardiovascular disease (CVD) is the leading cause of death in severe psychiatric disorders (depression, schizophrenia). Here, we provide evidence of how the effects of oxidative stress on fatty acid (FA) and one‐carbon (1‐C) cycle metabolism, which may initially represent adaptive responses, might underlie comorbidity between CVD and psychiatric disorders.

Successful pharmacologic treatment of major depressive disorder attenuates amygdala activation to negative facial expressions: a functional magnetic resonance imaging study.

OBJECTIVE Studies of the effects of pharmacotherapy for major depressive disorder (MDD) on limbic-subcortical-prefrontal brain networks show variable results. We quantified functional changes in the amygdala and the related limbic-subcortical-prefrontal structures after paroxetine treatment with functional magnetic resonance imaging relative to clinical responder status. METHOD We scanned 22 patients with unipolar, DSM-IV-defined MDD (men and women aged 25-55 years; 17-item Hamilton Depression Rating Scale [HDRS(17)] score > 18) at study entry and after 6 (T0) and 12 (T1) weeks of paroxetine treatment. Our paradigm contrasted negative (fearful, angry), happy, and neutral faces relative to scrambled faces. Twenty-one age-matched (± 2.5 y) and sex-matched controls were scanned once. Patients received open-label paroxetine 20 mg/d for 6 weeks (T0). Nonresponders at T0 were randomly assigned to receive double-blind true dose escalation (paroxetine 30-50 mg/d) or placebo dose escalation for another 6 weeks (T1). The study was conducted from July 2005 to February 2007. RESULTS At study entry, MDD patients showed increased ventral/limbic and decreased dorsal prefrontal activations to negative faces. At T0 and T1, respectively, 5/20 and 13/20 patients responded to paroxetine. After 12 weeks (at T1), overall amygdala activations remained unchanged relative to study entry. However, amygdala activations were significantly lower in treatment responders versus nonresponders (P = .001). Amygdala activations correlated with HDRS(17) scores (P < .04). Left amygdala activation correlated inversely with pregenual anterior cingulate cortex activation (P = .001). Dorsal cingulate gyrus and dorsolateral prefrontal activations increased after 6 and 12 weeks of treatment, regardless of clinical response. CONCLUSIONS Successful paroxetine treatment decreases amygdala activation, presumably by improved frontolimbic control, in line with selective serotonin reuptake inhibitor-induced increased functional connectivity between the pregenual anterior cingulated cortex, prefrontal cortex, and amygdala. Changes in amygdala activation when processing negative faces might serve as an indicator for improved frontolimbic control, which is required for clinical response. TRIAL REGISTRATION ISRCTN identifier: ISRCTN44111488.

Deep Brain Stimulation of the Ventral Anterior Limb of the Internal Capsule for Treatment-Resistant Depression: A Randomized Clinical Trial.

IMPORTANCE Patients with treatment-resistant depression (TRD) do not respond sufficiently to several consecutive treatments for major depressive disorder. Deep brain stimulation (DBS) is a promising treatment for these patients, but presently placebo effects cannot be ruled out. OBJECTIVE To assess the efficacy of DBS of the ventral anterior limb of the internal capsule (vALIC), controlling for placebo effects with active and sham stimulation phases. DESIGN, SETTING, AND PARTICIPANTS Twenty-five patients with TRD from 2 hospitals in the Netherlands were enrolled between March 22, 2010, and May 8, 2014. Patients first entered a 52-week open-label trial during which they received bilateral implants of 4 contact electrodes followed by optimization of DBS until a stable response was achieved. A randomized, double-blind, 12-week crossover phase was then conducted with patients receiving active treatment followed by sham or vice versa. Response and nonresponse to treatment were determined using intention-to-treat analyses. INTERVENTIONS Deep brain stimulation targeted to the vALIC. MAIN OUTCOMES AND MEASURES The change in the investigator-rated score of the 17-item Hamilton Depression Rating Scale (HAM-D-17) was the main outcome used in analysis of the optimization phase. The primary outcome of the crossover phase was the difference in the HAM-D-17 scores between active and sham DBS. The score range of this tool is 0 to 52, with higher scores representing more severe symptoms. Patients were classified as responders to treatment (≥50% decrease of the HAM-D-17 score compared with baseline) and partial responders (≥25 but <50% decrease of the HAM-D-17 score). RESULTS Of 25 patients included in the study, 8 (32%) were men; the mean (SD) age at inclusion was 53.2 (8.4) years. Mean HAM-D-17 scores decreased from 22.2 (95% CI, 20.3-24.1) at baseline to 15.9 (95% CI, 12.3-19.5) (P = .001), Montgomery-Åsberg Depression Rating Scale scores from 34.0 (95% CI, 31.8-36.3) to 23.8 (95% CI, 18.4-29.1) (P < .001), and Inventory of Depressive Symptomatology-Self-report scores from from 49.3 (95% CI, 45.4-53.2) to 38.8 (95% CI, 31.6-46.0) (P = .005) in the optimization phase. Following the optimization phase, which lasted 51.6 (22.0) weeks, 10 patients (40%) were classified as responders and 15 individuals (60%) as nonresponders. Sixteen patients entered the randomized crossover phase (9 responders [56%], 7 nonresponders [44%]). During active DBS, patients scored significantly lower on the HAM-D-17 scale (13.6 [95% CI, 9.8-17.4]) than during sham DBS (23.1 [95% CI, 20.6-25.6]) (P < .001). Serious adverse events included severe nausea during surgery (1 patient), suicide attempt (4 patients), and suicidal ideation (2 patients). CONCLUSIONS AND RELEVANCE Deep brain stimulation of the vALIC resulted in a significant decrease of depressive symptoms in 10 of 25 patients and was tolerated well. The randomized crossover design corroborates that vALIC DBS causes symptom reduction rather than sham. TRIAL REGISTRATION trialregister.nl Identifier: NTR2118.

Screening for depression in high-risk groups: prospective cohort study in general practice

BACKGROUND Currently only about half of the people who have major depressive disorder are detected during regular health care. Screening in high-risk groups might be a possible solution. AIMS To evaluate the effectiveness of selective screening for major depressive disorder in three high-risk groups in primary care: people with mental health problems, people with unexplained somatic complaints and people who frequently attend their general practitioner. METHOD Prospective cohort study among 2005 people in high-risk groups in three health centres in The Netherlands. RESULTS Of the 2005 people identified, 1687 were invited for screening and of these 780 participated. Screening disclosed 71 people with major depressive disorder: 36 (50.7%) already received treatment, 14 (19.7%) refused treatment and 4 individuals did not show up for an appointment. As a final result of the screening, 17 individuals (1% of 1687) started treatment for major depressive disorder. CONCLUSIONS Screening for depression in high-risk populations does not seem to be effective, mainly because of the low rates of treatment initiation, even if treatment is freely and easily accessible.

Preventing relapse in recurrent depression using mindfulness-based cognitive therapy, antidepressant medication or the combination: trial design and protocol of the MOMENT study

BackgroundDepression is a common psychiatric disorder characterized by a high rate of relapse and recurrence. The most commonly used strategy to prevent relapse/recurrence is maintenance treatment with antidepressant medication (mADM). Recently, it has been shown that Mindfulness-Based Cognitive Therapy (MBCT) is at least as effective as mADM in reducing the relapse/recurrence risk. However, it is not yet known whether combination treatment of MBCT and mADM is more effective than either of these treatments alone. Given the fact that most patients have a preference for either mADM or for MBCT, the aim of the present study is to answer the following questions. First, what is the effectiveness of MBCT in addition to mADM? Second, how large is the risk of relapse/recurrence in patients withdrawing from mADM after participating in MBCT, compared to those who continue to use mADM after MBCT?Methods/designTwo parallel-group, multi-center randomized controlled trials are conducted. Adult patients with a history of depression (3 or more episodes), currently either in full or partial remission and currently treated with mADM (6 months or longer) are recruited. In the first trial, we compare mADM on its own with mADM plus MBCT. In the second trial, we compare MBCT on its own, including tapering of mADM, with mADM plus MBCT. Follow-up assessments are administered at 3-month intervals for 15 months. Primary outcome is relapse/recurrence. Secondary outcomes are time to, duration and severity of relapse/recurrence, quality of life, personality, several process variables, and incremental cost-effectiveness ratio.DiscussionTaking into account patient preferences, this study will provide information about a) the clinical and cost-effectiveness of mADM only compared with mADM plus MBCT, in patients with a preference for mADM, and b) the clinical and cost-effectiveness of withdrawing from mADM after MBCT, compared with mADM plus MBCT, in patients with a preference for MBCT.Trial registrationClinicalTrials.gov: NCT00928980

Brain reward-system activation in response to anticipation and consumption of palatable food is altered by glucagon-like peptide-1 receptor activation in humans

To test the hypothesis that food intake reduction after glucagon‐like peptide‐1 (GLP‐1) receptor activation is mediated through brain areas regulating anticipatory and consummatory food reward.

Relationship between the hypothalamic-pituitary-adrenal-axis and fatty acid metabolism in recurrent depression

Alterations in hypothalamic-pituitary-adrenal (HPA)-axis activity and fatty acid (FA)-metabolism have been observed in (recurrent) major depressive disorder (MDD). Through the pathophysiological roles of FAs in the brain and cardiovascular system, a hypothesized relationship between HPA-axis activity and FA-metabolism could form a possible missing link accounting for the association of HPA-axis hyperactivity with recurrence and cardiovascular disease in MDD. In 137 recurrent MDD-patients and 73 age- and sex-matched controls, we therefore investigated associations between salivary cortisol (morning and evening) and the following indicators of FA-metabolism measured in the red blood cell membrane: (I) three main FAs [eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and arachidonic acid (AA)], and (II) structural FA indices (unsaturation, chain length, peroxidation) calculated from concentrations of 29 FAs to delineate overall FA-characteristics. In addition, we compared these associations in patients with those in controls. In patients, evening cortisol concentrations were significantly negatively associated with DHA (B=-1.358; SE=0.499; t=-2.72; p=.006), the unsaturation index (B=-0.021; SE=0.009; t=-2.42; p=.018), chain length index (B=-0.060; SE=0.025; t=-2.41; p=.019), and peroxidation index (B=-0.029; SE=0.012; t=-2.48; p=.015). The relations between cortisol and the latter three variables were significantly negative in patients relative to controls. Significance remained after correction for confounders. Our results suggest a relationship between HPA-axis activity and FA-metabolism in recurrent MDD. Future randomized experimental intervention studies using clinical outcome measures could help to further elucidate the suggested effects of hypercortisolemia in the brain and cardiovascular system in recurrent MDD.