Treating treatment-resistant patients with panic disorder and agoraphobia: A randomized controlled switching trial

Background: Nonresponsiveness to therapy is generally acknowledged, but only a few studies have tested switching to psychotherapy. This study is one of the first to examine the malleability of treatment-resistant patients using acceptance and commitment therapy (ACT). Methods: This was a randomized controlled trial that included 43 patients diagnosed with primary panic disorder and/or agoraphobia (PD/A) with prior unsuccessful state-of-the-art treatment (mean number of previous sessions = 42.2). Patients were treated with an ACT manual administered by novice therapists and followed up for 6 months. They were randomized to immediate treatment (n = 33) or a 4-week waiting list (n = 10) with delayed treatment (n = 8). Treatment consisted of eight sessions, implemented twice weekly over 4 weeks. Primary outcomes were measured with the Panic and Agoraphobia Scale (PAS), the Clinical Global Impression (CGI), and the Mobility Inventory (MI). Results: At post-treatment, patients who received ACT reported significantly more improvements on the PAS and CGI (d = 0.72 and 0.89, respectively) than those who were on the waiting list, while improvement on the MI (d = 0.50) was nearly significant. Secondary outcomes were consistent with ACT theory. Follow-up assessments indicated a stable and continued improvement after treatment. The dropout rate was low (9%). Conclusions: Despite a clinically challenging sample and brief treatment administered by novice therapists, patients who received ACT reported significantly greater changes in functioning and symptomatology than those on the waiting list, with medium-to-large effect sizes that were maintained for at least 6 months. These proof-of-principle data suggest that ACT is a viable treatment option for treatment-resistant PD/A patients. Further work on switching to psychotherapy for nonresponders is clearly needed. © 2015 S. Karger AG, Basel

Physical fitness is associated with neural activity during working memory performance in major depressive disorder

Background: Deficits in cognition like working memory (WM) are highly prevalent symptoms related to major depressive disorder (MDD). Neuroimaging studies have described frontoparietal abnormalities in patients with MDD as a basis for these deficits. Based on research in healthy adults, it is hypothesized that increased physical fitness might be a protective factor for these deficits in MDD. However, the relationship between physical fitness and WM-related neural activity and performance has not been tested in MDD, to date. Understanding these associations could inform the development of physical exercise interventions in MDD. Methods: Within a larger project, 111 (53female) MDD outpatients and 56 (34female) healthy controls performed an n-back task (0-, 1-, 2-, 3-back) during functional Magnetic Resonance Imaging. Physical fitness from a graded exercise test on a cycle ergometer was performed by 106 MDD patients. Results: Patients showed reduced performance particularly at high loads of the n-back WM task and prolonged reaction times at all n-back loads. A whole-brain interaction analysis of group by WM load revealed reduced neural activity in six frontoparietal clusters at medium and high WM loads in MDD patients compared to healthy controls. Analysis of covariance within the MDD sample showed that physical fitness was associated with neural activity in right and left superior parietal lobules. Externally defined Regions of Interest confirmed this analysis. Conclusions: Results indicate frontoparietal hypoactivity in MDD at high demands, arguing for decreased WM capacity. We demonstrate a parietal fitness correlate which could be used to guide future research on effects of exercise on cognitive functioning in MDD

Altered top-down and bottom-up processing of fear conditioning in panic disorder with agoraphobia

Background: Although several neurophysiological models have been proposed for panic disorder with agoraphobia (PD/AG), there is limited evidence from functional magnetic resonance imaging (fMRI) studies on key neural networks in PD/AG. Fear conditioning has been proposed to represent a central pathway for the development and maintenance of this disorder; however, its neural substrates remain elusive. The present study aimed to investigate the neural correlates of fear conditioning in PD/AG patients. Method: The blood oxygen level-dependent (BOLD) response was measured using fMRI during a fear conditioning task. Indicators of differential conditioning, simple conditioning and safety signal processing were investigated in 60 PD/AG patients and 60 matched healthy controls. Results: Differential conditioning was associated with enhanced activation of the bilateral dorsal inferior frontal gyrus (IFG) whereas simple conditioning and safety signal processing were related to increased midbrain activation in PD/AG patients versus controls. Anxiety sensitivity was associated positively with the magnitude of midbrain activation. Conclusions: The results suggest changes in top-down and bottom-up processes during fear conditioning in PD/AG that can be interpreted within a neural framework of defensive reactions mediating threat through distal (forebrain) versus proximal (midbrain) brain structures. Evidence is accumulating that this network plays a key role in the aetiopathogenesis of panic disorder

Short-term effects of video gaming on brain response during working memory performance

Breaks filled with different break activities often interrupt cognitive performance in everyday life. Previous studies have reported that both enhancing and deteriorating effects on challenging ongoing tasks such as working memory updating, depend on the type of break activity. However, neural mechanisms of these break-related alterations in working memory performance have not been studied, to date. Therefore, we conducted a brain imaging study to identify the neurobiological correlates of effects on the n-back working memory task related to different break activities. Before performing the n-back task in the magnetic resonance imaging (MRI) scanner, young adults were exposed to break activities in the MRI scanner involving (i) eyes-open resting, (ii) listening to music, and (iii) playing the video game “Angry Birds”. Heart rate was measured by a pulse oximeter during the experiment. We found that increased heart rate during gaming as well as decreased relaxation levels after a video gaming break was related to poorer n-back task performance, as compared to listening to music. On the neural level, video gaming reduced supplementary motor area activation during working memory performance. These results may indicate that video gaming during a break may affect working memory performance by interfering with arousal state and frontal cognitive control functions

converging evidence from an intermediate phenotype approach

Representing a phylogenetically old and very basic mechanism of inhibitory neurotransmission, glycine receptors have been implicated in the modulation of behavioral components underlying defensive responding toward threat. As one of the first findings being confirmed by genome-wide association studies for the phenotype of panic disorder and agoraphobia, allelic variation in a gene coding for the glycine receptor beta subunit (GLRB) has recently been associated with increased neural fear network activation and enhanced acoustic startle reflexes. On the basis of two independent healthy control samples, we here aimed to further explore the functional significance of the GLRB genotype (rs7688285) by employing an intermediate phenotype approach. We focused on the phenotype of defensive system reactivity across the levels of brain function, structure, and physiology. Converging evidence across both samples was found for increased neurofunctional activation in the (anterior) insular cortex in GLRB risk allele carriers and altered fear conditioning as a function of genotype. The robustness of GLRB effects is demonstrated by consistent findings across different experimental fear conditioning paradigms and recording sites. Altogether, findings provide translational evidence for glycine neurotransmission as a modulator of the brain’s evolutionary old dynamic defensive system and provide further support for a strong, biologically plausible candidate intermediate phenotype of defensive reactivity. As such, glycine-dependent neurotransmission may open up new avenues for mechanistic research on the etiopathogenesis of fear and anxiety disorders

Dimensional structure of bodily panic attack symptoms and their specific connections to panic cognitions, anxiety sensitivity and claustrophobic fears

Background. Previous studies of the dimensional structure of panic attack symptoms have mostly identified a respiratory and a vestibular/mixed somatic dimension. Evidence for additional dimensions such as a cardiac dimension and the allocation of several of the panic attack symptom criteria is less consistent. Clarifying the dimensional structure of the panic attack symptoms should help to specify the relationship of potential risk factors like anxiety sensitivity and fear of suffocation to the experience of panic attacks and the development of panic disorder. Method. In an outpatient multicentre study 350 panic patients with agoraphobia rated the intensity of each of the ten DSM-IV bodily symptoms during a typical panic attack. The factor structure of these data was investigated with nonlinear confirmatory factor analysis (CFA). The identified bodily symptom dimensions were related to panic cognitions, anxiety sensitivity and fear of suffocation by means of nonlinear structural equation modelling (SEM). Results. CFA indicated a respiratory, a vestibular/mixed somatic and a cardiac dimension of the bodily symptom criteria. These three factors were differentially associated with specific panic cognitions, different anxiety sensitivity facets and suffocation fear. Conclusions. Taking into account the dimensional structure of panic attack symptoms may help to increase the specificity of the associations between the experience of panic attack symptoms and various panic related constructs

D-cycloserine augmentation of exposure-based cognitive behavior therapy for anxiety, obsessive-compulsive, and posttraumatic stress disorders: a systematic review and meta-analysis of individual participant data

Importance: Whether and under which conditions D-cycloserine (DCS) augments the effects of exposure-based cognitive behavior therapy for anxiety, obsessive-compulsive, and posttraumatic stress disorders is unclear. Objective: To clarify whether DCS is superior to placebo in augmenting the effects of cognitive behavior therapy for anxiety, obsessive-compulsive, and posttraumatic stress disorders and to evaluate whether antidepressants interact with DCS and the effect of potential moderating variables. Data Sources: PubMed, EMBASE, and PsycINFO were searched from inception to February 10, 2016. Reference lists of previous reviews and meta-analyses and reports of randomized clinical trials were also checked. Study Selection: Studies were eligible for inclusion if they were (1) double-blind randomized clinical trials of DCS as an augmentation strategy for exposure-based cognitive behavior therapy and (2) conducted in humans diagnosed as having specific phobia, social anxiety disorder, panic disorder with or without agoraphobia, obsessive-compulsive disorder, or posttraumatic stress disorder. Data Extraction and Synthesis: Raw data were obtained from the authors and quality controlled. Data were ranked to ensure a consistent metric across studies (score range, 0-100). We used a 3-level multilevel model nesting repeated measures of outcomes within participants, who were nested within studies. Results: Individual participant data were obtained for 21 of 22 eligible trials, representing 1047 of 1073 eligible participants. When controlling for antidepressant use, participants receiving DCS showed greater improvement from pretreatment to posttreatment (mean difference, -3.62; 95% CI, -0.81 to -6.43; P = .01; d = -0.25) but not from pretreatment to midtreatment (mean difference, -1.66; 95% CI, -4.92 to 1.60; P = .32; d = -0.14) or from pretreatment to follow-up (mean difference, -2.98, 95% CI, -5.99 to 0.03; P = .05; d = -0.19). Additional analyses showed that participants assigned to DCS were associated with lower symptom severity than those assigned to placebo at posttreatment and at follow-up. Antidepressants did not moderate the effects of DCS. None of the prespecified patient-level or study-level moderators was associated with outcomes. Conclusions and Relevance: D-cycloserine is associated with a small augmentation effect on exposure-based therapy. This effect is not moderated by the concurrent use of antidepressants. Further research is needed to identify patient and/or therapy characteristics associated with DCS response.2018-05-0

Exercise therapy for Stress-related mental disorder, a randomised controlled trial in primary care

Background: to investigate whether a structured physical exercise programme (PEP) improves the recovery of general health in patients suffering from Stress-related Mental Disorder (SMD). Method: Study design: randomised open trial in general practice. Patients from two regions in the Netherlands were included between September 2003 and December 2005, and followed up for 12 weeks. Intervention: the patients were referred to a physical therapist for instruction in and monitoring of physical exercise of an intermediate intensity. Following the Dutch Guidelines for Healthy Physical Exercise, the patients were instructed to exercise at least five times a week, for at least 30 minutes per day. Control group: usual care from the GP Outcome: Primary: improvement of general health after 6 weeks according to the 'general health' dimension of the Short-Form 36. Secondary: total days off work, percentage that resumed work after 6 and 12 weeks, change in distress score and change in remaining SF36 dimensions after 6 and 12 weeks. Results: out of 102 randomised patients (mean age 43, 60 (59%) female), 70 (68%) completed the trial, of whom 31 were in the intervention group. After 6 weeks, the mean (SD) general health score was 54.6 (22.1) for the intervention group and 57.5 (19.2) for the controls. The corresponding effect size (Cohen's d with 95% confidence interval) from analysis of covariance was -0.06 (-0.41, 0.30) indicating no effect on general health. No significant effects of the intervention were detected for any secondary outcome parameter either. Conclusion: Notwithstanding the relatively high drop-out rate, our results suggest that referral to a physical therapist for structured physical exercise is not likely to be very effective in improving recovery from SMD. Trial registry: Current Controlled Trials ISRCTN15609105

Physical activity and depressive symptoms in adolescents: a prospective study

Background: The frequency of mental illness amongst adolescents and its potential long-term consequences make it an important topic to research in relation to risk and protective factors. Research on the relationship between physical activity and depressive symptoms in adolescents is limited. There is a particular lack of evidence from longitudinal studies. This study examines the relationship between depression and physical activity using the Research with East London Adolescents: Community Health Survey (RELACHS).Methods: This was a prospective cohort study. Participants were recruited from three Local Education Authority boroughs in East London in 2001 from year 7 (aged 11-12) and year 9 (aged 13-14) and were followed-up in 2003. All pupils in the 28 schools that took part were eligible for the study. Of the total 3,322 pupils eligible for the survey the overall response rate was 84% (2,789 pupils). A total of 2,093 (75%) pupils were also followed-up in 2003. The sample was multiethnic (73% of respondents were non-white) and deprived. Just under half of the sample was male (49%). Depressive symptoms were measured using the Short Moods and Feelings Questionnaire (SMFQ). Logistic regression analyses were used to examine the association between physical activity and depressive symptoms both cross-sectionally and longitudinally.Results: After adjustments, there was evidence for a cross-sectional association between physical activity and depressive symptoms for both boys and girls at baseline, with a decrease in the odds of depressive symptoms of about 8% for each additional hour of exercise undertaken per week (boys: odds ratio (OR) = 0.92, 95% CI 0.85 to 0.99; girls: OR = 0.92, 95% CI 0.85 to 1.00). There was no evidence for an association between a change in physical activity from baseline to follow-up and depressive symptoms at follow-up.Conclusions: This study provides some evidence for an association between level of physical activity and decreased depressive symptoms in adolescents. Further longitudinal research of these associations is required before physical activity can be recommended as an intervention for depression in adolescents

Depression does not affect the treatment outcome of CBT for panic and agoraphobia: results from a multicenter randomized trial

BACKGROUND: Controversy surrounds the questions whether co-occurring depression has negative effects on cognitive-behavioral therapy (CBT) outcomes in patients with panic disorder (PD) and agoraphobia (AG) and whether treatment for PD and AG (PD/AG) also reduces depressive symptomatology. METHODS: Post-hoc analyses of randomized clinical trial data of 369 outpatients with primary PD/AG (DSM-IV-TR criteria) treated with a 12-session manualized CBT (n = 301) and a waitlist control group (n = 68). Patients with comorbid depression (DSM-IV-TR major depression, dysthymia, or both: 43.2% CBT, 42.7% controls) were compared to patients without depression regarding anxiety and depression outcomes (Clinical Global Impression Scale [CGI], Hamilton Anxiety Rating Scale [HAM-A], number of panic attacks, Mobility Inventory [MI], Panic and Agoraphobia Scale, Beck Depression Inventory) at post-treatment and follow-up (categorical). Further, the role of severity of depressive symptoms on anxiety/depression outcome measures was examined (dimensional). RESULTS: Comorbid depression did not have a significant overall effect on anxiety outcomes at post-treatment and follow-up, except for slightly diminished post-treatment effect sizes for clinician-rated CGI (p = 0.03) and HAM-A (p = 0.008) when adjusting for baseline anxiety severity. In the dimensional model, higher baseline depression scores were associated with lower effect sizes at post-treatment (except for MI), but not at follow-up (except for HAM-A). Depressive symptoms improved irrespective of the presence of depression. CONCLUSIONS: Exposure-based CBT for primary PD/AG effectively reduces anxiety and depressive symptoms, irrespective of comorbid depression or depressive symptomatology