Nic J.A. van der Wee

Whole brain resting-state analysis reveals decreased functional connectivity in major depression.

Recently, both increases and decreases in resting-state functional connectivity have been found in major depression. However, these studies only assessed functional connectivity within a specific network or between a few regions of interest, while comorbidity and use of medication was not always controlled for. Therefore, the aim of the current study was to investigate whole-brain functional connectivity, unbiased by a priori definition of regions or networks of interest, in medication-free depressive patients without comorbidity. We analyzed resting-state fMRI data of 19 medication-free patients with a recent diagnosis of major depression (within 6 months before inclusion) and no comorbidity, and 19 age- and gender-matched controls. Independent component analysis was employed on the concatenated data sets of all participants. Thirteen functionally relevant networks were identified, describing the entire study sample. Next, individual representations of the networks were created using a dual regression method. Statistical inference was subsequently done on these spatial maps using voxel-wise permutation tests. Abnormal functional connectivity was found within three resting-state networks in depression: (1) decreased bilateral amygdala and left anterior insula connectivity in an affective network, (2) reduced connectivity of the left frontal pole in a network associated with attention and working memory, and (3) decreased bilateral lingual gyrus connectivity within ventromedial visual regions. None of these effects were associated with symptom severity or gray matter density. We found abnormal resting-state functional connectivity not previously associated with major depression, which might relate to abnormal affect regulation and mild cognitive deficits, both associated with the symptomatology of the disorder.

Regional brain volume in depression and anxiety disorders

CONTEXT Major depressive disorder (MDD), panic disorder, and social anxiety disorder are among the most prevalent and frequently co-occurring psychiatric disorders in adults and may have, at least in part, a common etiology. OBJECTIVE To identify the unique and shared neuroanatomical profile of depression and anxiety, controlling for illness severity, medication use, sex, age of onset, and recurrence. DESIGN Cross-sectional study. SETTING Netherlands Study of Depression and Anxiety. PARTICIPANTS Outpatients with MDD (n = 68), comorbid MDD and anxiety (n = 88), panic disorder, and/or social anxiety disorder without comorbid MDD (n = 68) and healthy controls (n = 65). MAIN OUTCOME MEASURES Volumetric magnetic resonance imaging was conducted for voxel-based morphometry analyses. We tested voxelwise for the effects of diagnosis, age at onset, and recurrence on gray matter density. Post hoc, we studied the effects of use of medication, illness severity, and sex. RESULTS We demonstrated lower gray matter volumes of the rostral anterior cingulate gyrus extending into the dorsal anterior cingulate gyrus in MDD, comorbid MDD and anxiety, and anxiety disorders without comorbid MDD, independent of illness severity, sex, and medication use. Furthermore, we demonstrated reduced right lateral inferior frontal volumes in MDD and reduced left middle/superior temporal volume in anxiety disorders without comorbid MDD. Also, patients with onset of depression before 18 years of age showed lower volumes of the subgenual prefrontal cortex. CONCLUSIONS Our findings indicate that reduced volume of the rostral-dorsal anterior cingulate gyrus is a generic effect in depression and anxiety disorders, independent of illness severity, medication use, and sex. This generic effect supports the notion of a shared etiology and may reflect a common symptom dimension related to altered emotion processing. Specific involvement of the inferior frontal cortex in MDD and lateral temporal cortex in anxiety disorders without comorbid MDD, on the other hand, may reflect disorder-specific symptom clusters. Early onset of depression is associated with a distinct neuroanatomical profile that may represent a vulnerability marker of depressive disorder.

Reduced Medial Prefrontal Cortex Volume in Adults Reporting Childhood Emotional Maltreatment

BACKGROUND Childhood emotional maltreatment (CEM) has been associated with a profound and enduring negative impact on behavioral and emotional functioning. Animal models have shown that adverse rearing conditions, such as maternal separation, can induce a cascade of long-term structural alterations in the brain, particularly in the hippocampus, amygdala, and prefrontal cortex. However, in humans, the neurobiological correlates of CEM are unknown. METHODS Using high-resolution T1-weighted 3T magnetic resonance imaging, anatomical scans and a whole-brain optimized voxel-based morphometry approach, we examined whether healthy control subjects and unmedicated patients with depression and/or anxiety disorders reporting CEM before age 16 (n = 84; age: mean = 38.7) displayed structural brain changes compared with control subjects and patients who reported no childhood abuse (n = 97; age: mean = 36.6). RESULTS We found that self-reported CEM is associated with a significant reduction in predominantly left dorsal medial prefrontal cortex volume, even in the absence of physical or sexual abuse during childhood. In addition, reduced medial prefrontal cortex in individuals reporting CEM is present in males and females, independent of concomitant psychopathology. CONCLUSIONS In this study, we show that CEM is associated with profound reductions of medial prefrontal cortex volume, suggesting that sustained inhibition of growth or structural damage can occur after exposure to CEM. Given the important role of the medial prefrontal cortex in the regulation of emotional behavior, our finding might provide an important link in understanding the increased emotional sensitivity in individuals reporting CEM.

Evidence-based pharmacological treatment of anxiety disorders, post-traumatic stress disorder and obsessive-compulsive disorder: A revision of the 2005 guidelines from the British Association for Psychopharmacology

This revision of the 2005 British Association for Psychopharmacology guidelines for the evidence-based pharmacological treatment of anxiety disorders provides an update on key steps in diagnosis and clinical management, including recognition, acute treatment, longer-term treatment, combination treatment, and further approaches for patients who have not responded to first-line interventions. A consensus meeting involving international experts in anxiety disorders reviewed the main subject areas and considered the strength of supporting evidence and its clinical implications. The guidelines are based on available evidence, were constructed after extensive feedback from participants, and are presented as recommendations to aid clinical decision-making in primary, secondary and tertiary medical care. They may also serve as a source of information for patients, their carers, and medicines management and formulary committees.

Neuroticism modulates amygdala-prefrontal connectivity in response to negative emotional facial expressions

Neuroticism is associated with the experience of negative affect and the development of affective disorders. While evidence exists for a modulatory role of neuroticism on task induced brain activity, it is unknown how neuroticism affects brain connectivity, especially the crucial coupling between the amygdala and the prefrontal cortex. Here we investigate this relation between functional connectivity and personality in response to negative facial expressions. Sixty healthy control participants, from the Netherlands Study on Depression and Anxiety (NESDA), were scanned during an emotional faces gender decision task. Activity and functional amygdala connectivity (psycho-physiological interaction [PPI]) related to faces of negative emotional valence (angry, fearful and sad) was compared to neutral facial expressions, while neuroticism scores were entered as a regressor. Activity for fearful compared to neutral faces in the dorsomedial prefrontal (dmPFC) cortex was positively correlated with neuroticism scores. PPI analyses revealed that right amygdala-dmPFC connectivity for angry and fearful compared to neutral faces was positively correlated with neuroticism scores. In contrast, left amygdala-anterior cingulate cortex (ACC) connectivity for angry, fearful and sad compared to neutral faces was negatively related to neuroticism levels. DmPFC activity has frequently been associated with self-referential processing in social cognitive tasks. Our results therefore suggest that high neurotic participants display stronger self-referential processing in response to negative emotional faces. Second, in line with previous reports on ACC function, the negative correlation between amygdala-ACC connectivity and neuroticism scores might indicate that those high in neuroticism display diminished control function of the ACC over the amygdala. These connectivity patterns might be associated with vulnerability to developing affective disorders such as depression and anxiety.

Hierarchical functional modularity in the resting‐state human brain

Functional magnetic resonance imaging (fMRI) studies have shown that anatomically distinct brain regions are functionally connected during the resting state. Basic topological properties in the brain functional connectivity (BFC) map have highlighted the BFCs small‐world topology. Modularity, a more advanced topological property, has been hypothesized to be evolutionary advantageous, contributing to adaptive aspects of anatomical and functional brain connectivity. However, current definitions of modularity for complex networks focus on nonoverlapping clusters, and are seriously limited by disregarding inclusive relationships. Therefore, BFCs modularity has been mainly qualitatively investigated. Here, we introduce a new definition of modularity, based on a recently improved clustering measurement, which overcomes limitations of previous definitions, and apply it to the study of BFC in resting state fMRI of 53 healthy subjects. Results show hierarchical functional modularity in the brain. Hum Brain Mapp, 2009.

Routine outcome monitoring and feedback on physical or mental health status: evidence and theory

OBJECTIVES Routine Outcome Monitoring (ROM) is an important quality tool for measuring outcome of treatment in health care. The objective of this article is to summarize the evidence base that supports the provision of feedback on ROM results to (mental) health care professionals and patients. Also, some relevant theoretical aspects are considered. METHODS Literature study (Pubmed, Medline, PsychINFO, Embase Psychiatry, 1975-2009) concerning randomized controlled trials (RTCs) of ROM and feedback on physical or mental health status of patients of all ages. Main search terms were routine outcome monitoring/measurement, feedback, health status measurement, patient reported outcome measures. RESULTS Included were 52 RCTs concerning ROM and feedback with adult or older patients: of these seven RCTs were exclusively focused on physical health and 45 RCTs (also) on the mental health of the patient, although not always in a mental health care setting or as primary outcome measure. There appears to be a positive impact of ROM on diagnosis and monitoring of treatment, and on communication between patient and therapist. Other results were less clear. There were no published RCTs on this topic with children or adolescents. CONCLUSIONS ROM appears especially effective for the monitoring of patients who are not doing well in therapy. Further research into this topic and the clinical-and cost-effectiveness of ROM is recommended, especially in mental health care for both adults and children. Also, more theory-driven research is needed with relevant conceptualizations such as Feedback Intervention Theory, Therapeutic Assessment.

Enhanced amygdala reactivity to emotional faces in adults reporting childhood emotional maltreatment

In the context of chronic childhood emotional maltreatment (CEM; emotional abuse and/or neglect), adequately responding to facial expressions is an important skill. Over time, however, this adaptive response may lead to a persistent vigilance for emotional facial expressions. The amygdala and the medial prefrontal cortex (mPFC) are key regions in face processing. However, the neurobiological correlates of face processing in adults reporting CEM are yet unknown. We examined amygdala and mPFC reactivity to emotional faces (Angry, Fearful, Sad, Happy, Neutral) vs scrambled faces in healthy controls and unmedicated patients with depression and/or anxiety disorders reporting CEM before the age of 16 years (n = 60), and controls and patients who report no childhood abuse (n = 75). We found that CEM was associated with enhanced bilateral amygdala reactivity to emotional faces in general, and independent of psychiatric status. Furthermore, we found no support for differential mPFC functioning, suggesting that amygdala hyper-responsivity to emotional facial perception in adults reporting CEM may be independent from top-down influences of the mPFC. These findings may be key in understanding the increased emotional sensitivity and interpersonal difficulties, that have been reported in individuals with a history of CEM.

A double blind comparison of venlafaxine and paroxetine in obsessive-compulsive disorder.

While the usefulness of clomipramine and selective serotonin reuptake inhibitors (SSRIs) in obsessive-compulsive disorder (OCD) has been established, the efficacy of serotonin-norepinephrine reuptake inhibitors remains to be determined. This report describes the first randomized double-blind comparison study of an SNRI in patients with obsessive-compulsive disorder. The current study compares the efficacy and tolerability of venlafaxine with paroxetine. One hundred and fifty patients with primary OCD according to DSM-IV criteria were randomly assigned in a 12-week double-blind trial to receive dosages titrated upward to 300 mg/d of venlafaxine (n = 75) or 60 mg/d of paroxetine (n = 75). Primary efficacy was assessed by the change from baseline on the Yale-Brown obsessive-compulsive scale (Y-BOCS). Other assessments throughout the trial included the Hamilton depression rating scale, and the Hamilton anxiety rating scale. An intent-to-treat, last-observation-carried-forward analysis demonstrated a mean decrease on the Y-BOCS of 7.2 ± 7.5 in the venlafaxine group and of 7.8 ± 5.4 in the paroxetine group. In both treatment groups, a responder rate (decrease > 35% on the Y-BOCS) of approximately 40% was found. There were no significant differences between venlafaxine and paroxetine with regard to response or responder rates. The incidence of adverse events for venlafaxine and paroxetine was comparable. The most common side effects for venlafaxine were somnolence, insomnia, a dry mouth, and sweating; and for paroxetine somnolence, sweating, nausea, and headache. These results show that venlafaxine was equally effective to paroxetine in treating patients with OCD. Venlafaxine may be a useful therapy for obsessive-compulsive patients, but is not superior to SSRIs.

Increased Serotonin and Dopamine Transporter Binding in Psychotropic Medication–Naïve Patients with Generalized Social Anxiety Disorder Shown by 123I-β-(4-Iodophenyl)-Tropane SPECT

There is circumstantial evidence for the involvement of serotonergic and dopaminergic systems in the pathophysiology of social anxiety disorder. In the present study, using SPECT imaging we examined the 123I-β-(4-iodophenyl)-tropane binding potential for the serotonin and dopamine transporters in patients with a generalized social anxiety disorder and in age- and sex-matched healthy controls. Methods: Twelve psychotropic medication–naïve patients with social anxiety disorder, generalized type (5 women and 7 men) and 12 sex- and age-matched healthy controls were studied. Volumes of interest were constructed on MRI-coregistered SPECT scans. Binding ratios were compared using the Mann–Whitney U test. Possible correlations between binding patterns and symptomatology were assessed using the Spearman rank correlation coefficient. Results: Significantly higher binding potentials were found for the serotonin in the left and right thalamus of patients. Patients had also a significantly higher binding potential for the dopamine transporter in the striatum. Conclusion: The present study provided direct evidence for abnormalities in both the dopaminergic and the serotonergic systems in patients with generalized social anxiety disorder.