Psychological therapies for panic disorder with or without agoraphobia in adults: a network meta-analysis.

BACKGROUND Panic disorder is characterised by the presence of recurrent unexpected panic attacks, discrete periods of fear or anxiety that have a rapid onset and include symptoms such as racing heart, chest pain, sweating and shaking. Panic disorder is common in the general population, with a lifetime prevalence of 1% to 4%. A previous Cochrane meta-analysis suggested that psychological therapy (either alone or combined with pharmacotherapy) can be chosen as a first-line treatment for panic disorder with or without agoraphobia. However, it is not yet clear whether certain psychological therapies can be considered superior to others. In order to answer this question, in this review we performed a network meta-analysis (NMA), in which we compared eight different forms of psychological therapy and three forms of a control condition. OBJECTIVES To assess the comparative efficacy and acceptability of different psychological therapies and different control conditions for panic disorder, with or without agoraphobia, in adults. SEARCH METHODS We conducted the main searches in the CCDANCTR electronic databases (studies and references registers), all years to 16 March 2015. We conducted complementary searches in PubMed and trials registries. Supplementary searches included reference lists of included studies, citation indexes, personal communication to the authors of all included studies and grey literature searches in OpenSIGLE. We applied no restrictions on date, language or publication status. SELECTION CRITERIA We included all relevant randomised controlled trials (RCTs) focusing on adults with a formal diagnosis of panic disorder with or without agoraphobia. We considered the following psychological therapies: psychoeducation (PE), supportive psychotherapy (SP), physiological therapies (PT), behaviour therapy (BT), cognitive therapy (CT), cognitive behaviour therapy (CBT), third-wave CBT (3W) and psychodynamic therapies (PD). We included both individual and group formats. Therapies had to be administered face-to-face. The comparator interventions considered for this review were: no treatment (NT), wait list (WL) and attention/psychological placebo (APP). For this review we considered four short-term (ST) outcomes (ST-remission, ST-response, ST-dropouts, ST-improvement on a continuous scale) and one long-term (LT) outcome (LT-remission/response). DATA COLLECTION AND ANALYSIS As a first step, we conducted a systematic search of all relevant papers according to the inclusion criteria. For each outcome, we then constructed a treatment network in order to clarify the extent to which each type of therapy and each comparison had been investigated in the available literature. Then, for each available comparison, we conducted a random-effects meta-analysis. Subsequently, we performed a network meta-analysis in order to synthesise the available direct evidence with indirect evidence, and to obtain an overall effect size estimate for each possible pair of therapies in the network. Finally, we calculated a probabilistic ranking of the different psychological therapies and control conditions for each outcome. MAIN RESULTS We identified 1432 references; after screening, we included 60 studies in the final qualitative analyses. Among these, 54 (including 3021 patients) were also included in the quantitative analyses. With respect to the analyses for the first of our primary outcomes, (short-term remission), the most studied of the included psychological therapies was CBT (32 studies), followed by BT (12 studies), PT (10 studies), CT (three studies), SP (three studies) and PD (two studies).The quality of the evidence for the entire network was found to be low for all outcomes. The quality of the evidence for CBT vs NT, CBT vs SP and CBT vs PD was low to very low, depending on the outcome. The majority of the included studies were at unclear risk of bias with regard to the randomisation process. We found almost half of the included studies to be at high risk of attrition bias and detection bias. We also found selective outcome reporting bias to be present and we strongly suspected publication bias. Finally, we found almost half of the included studies to be at high risk of researcher allegiance bias.Overall the networks appeared to be well connected, but were generally underpowered to detect any important disagreement between direct and indirect evidence. The results showed the superiority of psychological therapies over the WL condition, although this finding was amplified by evident small study effects (SSE). The NMAs for ST-remission, ST-response and ST-improvement on a continuous scale showed well-replicated evidence in favour of CBT, as well as some sparse but relevant evidence in favour of PD and SP, over other therapies. In terms of ST-dropouts, PD and 3W showed better tolerability over other psychological therapies in the short term. In the long term, CBT and PD showed the highest level of remission/response, suggesting that the effects of these two treatments may be more stable with respect to other psychological therapies. However, all the mentioned differences among active treatments must be interpreted while taking into account that in most cases the effect sizes were small and/or results were imprecise. AUTHORS' CONCLUSIONS There is no high-quality, unequivocal evidence to support one psychological therapy over the others for the treatment of panic disorder with or without agoraphobia in adults. However, the results show that CBT - the most extensively studied among the included psychological therapies - was often superior to other therapies, although the effect size was small and the level of precision was often insufficient or clinically irrelevant. In the only two studies available that explored PD, this treatment showed promising results, although further research is needed in order to better explore the relative efficacy of PD with respect to CBT. Furthermore, PD appeared to be the best tolerated (in terms of ST-dropouts) among psychological treatments. Unexpectedly, we found some evidence in support of the possible viability of non-specific supportive psychotherapy for the treatment of panic disorder; however, the results concerning SP should be interpreted cautiously because of the sparsity of evidence regarding this treatment and, as in the case of PD, further research is needed to explore this issue. Behaviour therapy did not appear to be a valid alternative to CBT as a first-line treatment for patients with panic disorder with or without agoraphobia.

Exercise and Mood: Exploring the Role of Exercise in Regulating Stress Reactivity in Bipolar Disorder

Bipolar Disorder (BD) is a recurrent and debilitating psychological disorder characterized by a chronic dysregulation of mood with fluctuations between extremely low (e.g., depression) and extremely elevated mood states (e.g., mania), and ranks as the 6th leading cause of disability in the world. Although research has consistently shown that exercise may have antidepressant and stress-attenuating benefits in other psychiatric illnesses (e.g., depression, anxiety), these benefits have not been directly investigated for BD. The current study represents the first known investigation to examine this relationship. Single-participant designs, with crossover and interaction treatment components (i.e., A/B/A/B/A, A/C/A/C/A, A/B/A/C/A, or A/C/A/B/A) were utilized to investigate the impact of participation in a prescribed regimen of exercise (EP) versus standard behavioral activation (SBA; i.e., non-exercise activity) has on stress perception and reactivity, and mood stability in a sample of individuals with BD. Individuals completed four total weeks of treatment, and psychophysiological measures of reactivity were recorded during a laboratory stress task (i.e., backward counting task) prior to and following each two-week intervention phase. No appreciable differences were found between levels of exercise participation between treatment groups. Interestingly, symptoms of depressed mood (BDI-II scores) decreased at similar rates following 4 weeks of treatment for all participants. BDI-II decreases were found to be most correlated with elective exercise participation, although this relationship was not significant. Regarding stress reactivity, elective participation in mild to moderate intensity exercise was found to reduce an individual’s perception of stress reactivity to an acute stressor, while participation in a prescribed program of exercise was more effective in reducing physiological response to the same task. Utilizing multiple forms of behavioral activation simultaneously was found to be most effective in decreasing perception of stress reactivity, and may also result in a positive change in the use of adaptive versus maladaptive coping strategies. Participation in a 4-week program of exercise appeared to provide the most benefit, consistent with exercise habituation theories. Overall, current findings provide preliminary support for the prophylactic benefits of including a prescribed and monitored program of exercise as an adjunct treatment for individuals with BD. Larger scale research is needed to more clearly determine the impact of exercise on stress reactivity and mood episode relapse in individuals with BD.

Back pain in migrant farmworker families and farmworker high school students from Starr County, Texas

Back symptoms are a major global public health problem with the lifetime prevalence ranging between 50-80%. Research suggests that work-related factors contribute to the occurrence of back pain in various industries. Despite the hazardous nature, strenuous tasks, and awkward postures associated with farm work, little is known about back injury and symptoms in farmworker adults and children. Research in the United States is particularly limited. This is a concern given the large proportion of migrant farmworkers in the United States without adequate access to healthcare as well as a substantial number of youth working in agriculture. The present study describes back symptoms and identifies work-related factors associated with back pain in migrant farmworker families and farmworker high school students from Starr County, TX. Two separate datasets were used from two cohort studies "Injury and Illness Surveillance in Migrant Farmworkers (MANOS)" (study A: n=267 families) and "South Texas Adolescent Rural Research Study (STARRS)" (study B: n=345). Descriptive and inferential statistics including multivariable logistic regression were used to identify work-related factors associated with back pain in each study. In migrant farmworker families, the prevalence of chronic back pain during the last migration season ranged from 9.5% among youngest children to 33.3% among mothers. Chronic back pain was significantly associated with increasing age; fairly bad/very bad quality of sleep while migrating; fewer than eight hours of sleep at home in Starr County, TX; depressive symptoms while migrating; self-provided water for washing hands/drinking; weeding at work; and exposure to pesticide drift/direct spray. Among farmworker adolescents, the prevalence of severe back symptoms was 15.7%. Severe back symptoms were significantly associated with being female; history of a prior accident/back injury; feeling tense, stressed, or anxious sometimes/often; lifting/carrying heavy objects not at work; current tobacco use; increasing lifetime number of migrant farmworker years; working with/around knives; and working on corn crops. Overall, results support that associations between work-related exposures and chronic back pain and severe back symptoms remain after controlling for the effect of non-work exposures in farmworker populations. ^

Long-term hyperexcitability of sensory and motor axons in Aplysia californica: Induction by axotomy, serotonin, and transient depolarization

Neuropathic pain is a debilitating neurological disorder that may appear after peripheral nerve trauma and is characterized by persistent, intractable pain. The well-studied phenomenon of long-term hyperexcitability (LTH), in which sensory somata become hyperexcitable following peripheral nerve injury may be important for both chronic pain and long-lasting memory formation, since similar cellular alterations take place after both injury and learning. Though axons have previously been considered simple conducting cables, spontaneous afferent signals develop from some neuromas that form at severed nerve tips, indicating intrinsic changes in sensory axonal excitability may contribute to this intractable pain. Here we show that nerve transection, exposure to serotonin, and transient depolarization induce long-lasting sensory axonal hyperexcitability that is localized to the treated nerve segment and requires local translation of new proteins. Long-lasting functional plasticity may be a general property of axons, since both injured and transiently depolarized motor axons display LTH as well. Axonal hyperexcitability may represent an adaptive mechanism to overcome conduction failure after peripheral injury, but also displays key features shared with cellular analogues of memory including: site-specific changes in neuronal function, dependence on transient, focal depolarization for induction, and requirement for synthesis of new proteins for expression of long-lasting effects. The finding of axonal hyperexcitability after nerve injury sheds new light on the clinical problem of chronic neuropathic pain, and provides more support for the hypothesis that mechanisms of long-term memory storage evolved from primitive adaptive responses to injury. ^

Frequency, severity and distress of dialysis-related symptoms reported by patients on hemodialysis

Purpose. To determine which symptoms are the most reported, occur most frequently, have the greatest severity, and cause the most bother for hemodialysis (HD) patients and to determine if the symptoms experienced differ between the first (HD 1) and second (HD 2) treatments of the week. ^ Design. An observational, comparative design was used to determine participants' HD symptoms experience on HD 1 and HD 2, and the effect of the symptom experience on Quality of Life (QOL). One hundred subjects were recruited from five dialysis centers. ^ Methods. The adapted Dialysis Frequency, Severity and Symptom Burden Index (DFSSBI) and the Medical Outcomes Study Short Form 36 (MOS SF 36) were administered (N = 99) on HD 1 and the DFSSBI again on HD 2. Data were analyzed for significance among symptoms experience test scores in relation to HD 1 and HD 2, QOL, and gender and age. ^ Results. Of 31 symptoms assessed, respondents reported an average of 9.69 symptoms on HD 1 and 7.51 symptoms on HD 2. Overall, more symptoms were reported, and were more frequent, severe and bothersome on HD 1 when the level of metabolic waste is highest. The most reported symptoms included tiredness, dry skin, difficulty falling asleep, itching, numbness/tingling, difficulty staying asleep, decreased interest in sex, and bone/joint pain. Females scored consistently higher than males in the four symptom dimensions. The respondents reported about the same as the population norm (50) on the physical component summary score of the MOS SF 36 and higher than the norm (65.23) on the mental component summary score. ^ Conclusion. The study findings highlighted the fact that hemodialysis patients experience multiple symptoms that can be frequent, severe, and bothersome. Interventions should be developed and tested to reduce symptom burden and improve QOL. ^

A methodologic study of pain assessment in Anglo and Hispanic children with cancer

There is growing clinical evidence that even young children experience pain and accompanying anxiety. Few instruments have been validated to assess pain characteristics in children. The study of related demographic, illness, psychologic and parental factors in children has also been limited. This study examines the reliability and validity of pain assessment tools in an outpatient pediatric cancer population. A total of 78 children from three to fifteen years of age were observed and interviewed about the pain of invasive procedures. The effect of cultural factors and the stress of acculturation were examined by comparing data from two cultural groups, Anglo and Hispanic.^ Spielberger State-Trait Anxiety Scales were administered to children and parents prior to an invasive procedure. The Procedure Behavioral Checklist (PBCL) was used for observation of the child's response during the procedure. The Children's Procedural Interview (CPI) which contains items on the PBCL and visual analogues (scales of faces indicating varying degrees of pain and anxiety) was administered following the procedure.^ Reliability coefficients for Anglos were.78 on the PBCL,.79 on the CPI and.85 on the visual analogue scales. For Hispanics, the reliability for the PBCL was.54, while the CPI had a reliability of.72 and the visual analogue scales,.87. Construct validity was demonstrated by high correlations between the PBCL and CPI scores for both ethnic groups (.66 for Anglos and.64 for Hispanics) and by the significant correlation of State anxiety scores with both PBCL and CPI scores. Age was inversely correlated with PBCL and CPI scores for both ethnic groups. Hispanic parents' anxiety scores were higher than Anglo parents, but were not highly correlated with their child's PBCL, CPI or State-Trait anxiety scores. Caregivers' ratings were correlated with the PBCL scores for Anglos but not for Hispanics.^ The findings of this study indicate that pain responses may be reliably assessed using both observational and self-report methods in children, though differences in Anglo and Hispanic cultures exist. Differences in pain symptomatology and assessment in the two cultural groups warrant further study. ^

Central pain augmentation in fibromyalgia during subjectively-matched mechanical stimulation

The precise pathophysiology of fibromyalgia, a syndrome characterized by, among other symptoms, chronic widespread pain, remains to be elucidated (Abeles et al., 2007). The fact that, when subjected to the same amount of stimulation, patients show enhanced brain responses as compared to controls provides evidence of central pain augmentation in this syndrome. We aimed to characterize brain response differences when stimulation is adjusted to elicit similar subjective levels of pain in both groups.

Agmatine reverses pain induced by inflammation, neuropathy, and spinal cord injury

Antagonists of glutamate receptors of the N-methyl-d-aspartate subclass (NMDAR) or inhibitors of nitric oxide synthase (NOS) prevent nervous system plasticity. Inflammatory and neuropathic pain rely on plasticity, presenting a clinical opportunity for the use of NMDAR antagonists and NOS inhibitors in chronic pain. Agmatine (AG), an endogenous neuromodulator present in brain and spinal cord, has both NMDAR antagonist and NOS inhibitor activities. We report here that AG, exogenously administered to rodents, decreased hyperalgesia accompanying inflammation, normalized the mechanical hypersensitivity (allodynia/hyperalgesia) produced by chemical or mechanical nerve injury, and reduced autotomy-like behavior and lesion size after excitotoxic spinal cord injury. AG produced these effects in the absence of antinociceptive effects in acute pain tests. Endogenous AG also was detected in rodent lumbosacral spinal cord in concentrations similar to those previously detected in brain. The evidence suggests a unique antiplasticity and neuroprotective role for AG in processes underlying persistent pain and neuronal injury.