Effects of a Transdiagnostic Internet Intervention («velibra») for Anxiety Disorders in Primary Care: Results of a Randomized Controlled Trial

Internet-based cognitive behavioral self-help treatment (ICBT) for anxiety disorders has shown promising results in several trials, but there is yet a lack of studies of ICBT in „real world” primary care settings. In this randomized controlled trial we recruited participants through general practitioners. The aim of the study was to examine whether treatment-as-usual (TAU) in primary care settings plus ICBT is superior to TAU alone in reducing anxiety symptoms and other outcome measures among individuals meeting diagnostic criteria of a least one of three anxiety disorders (social anxiety disorder, panic disorder with or without agoraphobia, generalized anxiety disorder). 150 adults fulfilling diagnostic criteria for a least one of the anxiety disorders according to a diagnostic interview are randomly assigned to one of the two conditions: TAU plus ICBT versus TAU. Randomization is stratified by primary disorder, medication (yes/no) and concurrent psychotherapy. ICBT consists of a transdiagnostic and tailored Internet-based self-help program for several anxiety disorders which also includes cognitive bias modification for interpretation (CBM-I). Primary outcomes are symptoms of disorder-specific anxiety measures and diagnostic status after the intervention (9 weeks). Secondary outcomes include primary outcomes at 3-month follow-up and secondary measures such as general symptomatology, depression, quality of life, adherence to ICBT and satisfaction with ICBT. The study is currently being completed. Primary results along with results for specific subgroups (e.g. primary diagnosis, concurrent medication and/or psychotherapy) will be presented and discussed.

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.

The effects of antipsychotic medications on eye movements in schizophrenia

Schizophrenia is the most prevalent mental disorder in the world, affecting approximately one percent of the population. Antipsychotic medications have successfully treated schizophrenic psychotic symptoms for years, however their positive effects on cognitive dysfunction, a core feature of schizophrenia, are inconclusive. Recent studies have shown that improved cognitive functioning is most often associated with the best long-term prognosis. Thus, clarifying the cognitive effects of commonly prescribed antipsychotic medications is pivotal to improving quality of life and long-term care of schizophrenic patients.^ Previous studies on cognitive dysfunction in schizophrenia utilized complex neuropsychological tasks requiring many intact areas of the brain for proper completion. These complexities make interpretation of acquired data difficult. Recently, eye movements have been identified as a more effective surrogate for investigating cognitive functioning. Eye movements are easily measured, require known discrete areas of the brain for processing, and are ubiquitous. They influence what we attend to and process in the brain; thus they are a pivotal aspect of cognitive functioning. This study sought to examine the effects of antipsychotic medications on eye movements in forty-two schizophrenic patients. These patients were divided equally into the three tested medication groups: haloperidol, olanzapine, and aripiprazole. To the extent possible, these groups were further separated into task-impaired and task-nonimpaired subgroups, and again analyzed. Clinical and neuropsychological scales were administered to assess clinical and eye movement changes.^ The results of this study found the olanzapine-treated group exhibited superior cognitive effects to the aripiprazole-treated group, who was superior to the haloperidol-treated group. Furthermore, upon subdivision into cognitively impaired and nonimpaired subgroups, both olanzapine-treated subgroups continued to show improvement, while only the aripiprazole-treated impaired subgroup showed cognitive benefit. The haloperidol-treated nonimpaired subgroup actually demonstrated worsening effects. Interestingly, despite the cognitive decline of some subgroups, the clinical assessment results indicated virtually all subgroups exhibited significant clinical improvement. Hence, careful selection of an antipsychotic medication is crucial, as this study shows some treatments may help whereas others may hinder cognitive functioning in schizophrenia. ^ The results of this study are extremely important given the relationship between cognitive improvement and long-term prognosis in schizophrenia. Finally, and perhaps most importantly, these results indicate that clinical improvement is not necessarily indicative of cognitive improvement. ^

Effects of treatment on orienting in Parkinson disease

Parkinson disease (PD) is a movement disorder affecting over one million Americans, and 1% of our population over 60 years of age. Currently, PD has an unknown cause, no predictive biomarker, and no cure, yet there are effective treatments (medicine and surgery) to chronically manage the motor symptoms. But, PD patients also develop cognitive symptoms (e.g., distractibility, executive dysfunction) that remain untreated or may decline as a result of treating the motor symptoms. To address this important issue, I measured covert orienting of attention and overt eye movements in PD patients to assess the patients' ability to automatically detect stimuli in their visual field, to predict and attend to where the stimuli would appear, and to volitionally look somewhere else. ^ PD patients completed the cognitive tasks under multiple treatment conditions, and their performance was compared to healthy adults. PD patients first completed the tasks after they had withdrawn from medication. Their unmedicated performance revealed exaggerated automatic orienting, poor predictability, and weak volitional orienting. PD patients then repeated the tasks while medication was giving its peak benefit. The medication returned automatic covert orienting toward normal but did not improve volitional covert orienting. Several PD patients completed the tasks a third time after receiving surgery (specifically, implantation of stimulating electrodes in a subcortical brain region to alleviate motor symptoms). The stimulation (without medication) returned automatic orienting toward normal, did not change predictability, and further impaired volitional orienting. Taken together, treatments prescribed to alleviate the motor symptoms (a patient's primary concern) only improve some cognitive functions. Future studies may establish criteria to predict which patients are more likely to have cognitive benefit from medication over surgery, or vice versa. ^ I have also hypothesized an anatomical model relating orienting circuitry to abnormal PD circuitry and the therapeutic targets. My results suggest medication is more effective restoring the orienting circuitry than stimulation. Further, automatic and volitional orienting abilities seem to be modulated independently, which differs from an earlier model proposing a dependent, inverse relationship. My results are further discussed in terms of response inhibition, response selection, and the location of the selection. ^

The effects of respiratory ailments and income on depression in a nationally representative sample

Asthma, chronic obstructive pulmonary disorder, sinusitis and hay fever have previously been documented as risk factors for future depression in a wide variety of populations. Likewise, belonging to a higher income category has been found to place a person at risk for any type of depression. This study investigates whether an interactive effect between personal income and the presence of any of the four aforementioned respiratory illnesses contribute to an increased risk for depression. Using the National Health and Nutrition Health Examination Survey cross-sectional survey for 2005-2006, analysis of an interaction term for each illness in the presence of confounding factors such as age, smoking status, past or present diagnosis of diabetes, coronary heart disease and heart attack was made within six distinct racial/ethnic and sex subgroups. Generally, interaction terms were found to be non-significant in nature, except hay fever and COPD where in a few subgroups where the interaction term conferred a protective or risk influence depending on the subgroup analyzed. These findings are discussed in light of potential social costs of having certain respiratory illnesses by individuals in higher income categories and the effect of severity within each illness on the resulting risk or protective effect of the interaction term.^

Complexity analysis of spontaneous brain activity: effects of depression and antidepressant treatment

Magnetoencephalography (MEG) allows the real-time recording of neural activity and oscillatory activity in distributed neural networks. We applied a non-linear complexity analysis to resting-state neural activity as measured using whole-head MEG. Recordings were obtained from 20 unmedicated patients with major depressive disorder and 19 matched healthy controls. Subsequently, after 6 months of pharmacological treatment with the antidepressant mirtazapine 30 mg/day, patients received a second MEG scan. A measure of the complexity of neural signals, the Lempel–Ziv Complexity (LZC), was derived from the MEG time series. We found that depressed patients showed higher pre-treatment complexity values compared with controls, and that complexity values decreased after 6 months of effective pharmacological treatment, although this effect was statistically significant only in younger patients. The main treatment effect was to recover the tendency observed in controls of a positive correlation between age and complexity values. Importantly, the reduction of complexity with treatment correlated with the degree of clinical symptom remission. We suggest that LZC, a formal measure of neural activity complexity, is sensitive to the dynamic physiological changes observed in depression and may potentially offer an objective marker of depression and its remission after treatment.

Silencing microRNA-134 produces neuroprotective and prolonged seizure-suppressive effects

Temporal lobe epilepsy is a common, chronic neurological disorder characterized by recurrent spontaneous seizures. MicroRNAs (miRNAs) are small, noncoding RNAs that regulate post-transcriptional expression of protein-coding mRNAs, which may have key roles in the pathogenesis of neurological disorders. In experimental models of prolonged, injurious seizures (status epilepticus) and in human epilepsy, we found upregulation of miR-134, a brain-specific, activity-regulated miRNA that has been implicated in the control of dendritic spine morphology. Silencing of miR-134 expression in vivo using antagomirs reduced hippocampal CA3 pyramidal neuron dendrite spine density by 21% and rendered mice refractory to seizures and hippocampal injury caused by status epilepticus. Depletion of miR-134 after status epilepticus in mice reduced the later occurrence of spontaneous seizures by over 90% and mitigated the attendant pathological features of temporal lobe epilepsy. Thus, silencing miR-134 exerts prolonged seizure-suppressant and neuroprotective actions; determining whether these are anticonvulsant effects or are truly antiepileptogenic effects requires additional experimentation.

Cladistic association analysis of Y chromosome effects on alcohol dependence and related personality traits

Association between Y chromosome haplotype variation and alcohol dependence and related personality traits was investigated in a large sample of psychiatrically diagnosed Finnish males. Haplotypes were constructed for 359 individuals using alleles at eight loci (seven microsatellite loci and a nucleotide substitution in the DYZ3 alphoid satellite locus). A cladogram linking the 102 observed haplotype configurations was constructed by using parsimony with a single-step mutation model. Then, a series of contingency tables nested according to the cladogram hierarchy were used to test for association between Y haplotype and alcohol dependence. Finally, using only alcohol-dependent subjects, we tested for association between Y haplotype and personality variables postulated to define subtypes of alcoholism—antisocial personality disorder, novelty seeking, harm avoidance, and reward dependence. Significant association with alcohol dependence was observed at three Y haplotype clades, with significance levels of P = 0.002, P = 0.020, and P = 0.010. Within alcohol-dependent subjects, no relationship was revealed between Y haplotype and antisocial personality disorder, novelty seeking, harm avoidance, or reward dependence. These results demonstrate, by using a fully objective association design, that differences among Y chromosomes contribute to variation in vulnerability to alcohol dependence. However, they do not demonstrate an association between Y haplotype and the personality variables thought to underlie the subtypes of alcoholism.

Developmental disorder associated with increased cellular nucleotidase activity

Four unrelated patients are described with a syndrome that included developmental delay, seizures, ataxia, recurrent infections, severe language deficit, and an unusual behavioral phenotype characterized by hyperactivity, short attention span, and poor social interaction. These manifestations appeared within the first few years of life. Each patient displayed abnormalities on EEG. No unusual metabolites were found in plasma or urine, and metabolic testing was normal except for persistent hypouricosuria. Investigation of purine and pyrimidine metabolism in cultured fibroblasts derived from these patients showed normal incorporation of purine bases into nucleotides but decreased incorporation of uridine. De novo synthesis of purines and cellular phosphoribosyl pyrophosphate content also were moderately decreased. The distribution of incorporated purines and pyrimidines did not reveal a pattern suggestive of a deficient enzyme activity. Assay of individual enzymes in fibroblast lysates showed no deficiencies. However, the activity of cytosolic 5′-nucleotidase was elevated 6- to 10-fold. Based on the possibility that the observed increased catabolic activity and decreased pyrimidine salvage might be causing a deficiency of pyrimidine nucleotides, the patients were treated with oral pyrimidine nucleoside or nucleotide compounds. All patients showed remarkable improvement in speech and behavior as well as decreased seizure activity and frequency of infections. A double-blind placebo trial was undertaken to ascertain the efficacy of this supplementation regimen. Upon replacement of the supplements with placebo, all patients showed rapid regression to their pretreatment states. These observations suggest that increased nucleotide catabolism is related to the symptoms of these patients, and that the effects of this increased catabolism are reversed by administration of uridine.

Hereditary hemochromatosis: Effects of C282Y and H63D mutations on association with β2-microglobulin, intracellular processing, and cell surface expression of the HFE protein in COS-7 cells

Hereditary hemochromatosis (HH) is the most common autosomal recessive disorder known in humans. A candidate gene for HH called HFE has recently been cloned that encodes a novel member of the major histocompatibility complex class I family. Most HH patients are homozygous for a Cys-282→Tyr (C282Y) mutation in HFE gene, which has been shown to disrupt interaction with β2-microglobulin; a second mutation, His-63→Asp (H63D), is enriched in HH patients who are heterozygous for C282Y mutation. The aims of this study were to determine the effects of the C282Y and H63D mutations on the cellular trafficking and degradation of the HFE protein in transfected COS-7 cells. The results indicate that, while the wild-type and H63D HFE proteins associate with β2-microglobulin and are expressed on the cell surface of COS-7 cells, these capabilities are lost by the C282Y HFE protein. We present biochemical and immunofluorescence data that indicate that the C282Y mutant protein: (i) is retained in the endoplasmic reticulum and middle Golgi compartment, (ii) fails to undergo late Golgi processing, and (iii) is subject to accelerated degradation. The block in intracellular transport, accelerated turnover, and failure of the C282Y protein to be presented normally on the cell surface provide a possible basis for impaired function of this mutant protein in HH.

Interplay of structure and disorder in cochaperonin mobile loops.

Protein-protein interactions typically are characterized by highly specific interfaces that mediate binding with precisely tuned affinities. Binding of the Escherichia coli cochaperonin GroES to chaperonin GroEL is mediated, at least in part, by a mobile polypeptide loop in GroES that becomes immobilized in the GroEL/GroES/nucleotide complex. The bacteriophage T4 cochaperonin Gp31 possesses a similar highly flexible polypeptide loop in a region of the protein that shows low, but significant, amino acid similarity with GroES and other cochaperonins. When bound to GroEL, a synthetic peptide representing the mobile loop of either GroES or Gp31 adopts a characteristic bulged hairpin conformation as determined by transferred nuclear Overhauser effects in NMR spectra. Thermodynamic considerations suggest that flexible disorder in the cochaperonin mobile loops moderates their affinity for GroEL to facilitate cycles of chaperonin-mediated protein folding.

Genetic variation in vulnerability to the behavioral effects of neonatal hippocampal damage in rats.

We explored how two independent variables, one genetic (i.e., specific rat strains) and another environmental (i.e., a developmental excitotoxic hippocampal lesion), contribute to phenotypic variation. Sprague-Dawley (SD), Fischer 344 (F344), and Lewis rats underwent two grades of neonatal excitotoxic damage: small and large ventral hippocampal (SVH and LVH) lesions. Locomotion was tested before puberty [postnatal day 35 (P35)] and after puberty (P56) following exposure to a novel environment or administration of amphetamine. The behavioral effects were strain- and lesion-specific. As shown previously, SD rats with LVH lesions displayed enhanced spontaneous and amphetamine-induced locomotion as compared with controls at P56, but not at P35. SVH lesions in SD rats had no effect at any age. In F344 rats with LVH lesions, enhanced spontaneous and amphetamine-induced locomotion appeared early (P35) and was exaggerated at P56. SVH lesions in F344 rats resulted in a pattern of effects analogous to LVH lesions in SD rats--i.e., postpubertal onset of hyperlocomotion (P56). In Lewis rats, LVH lesions had no significant effect on novelty- or amphetamine-induced locomotion at any age. These data show that the degree of genetic predisposition and the extent of early induced hippocampal defect contribute to the particular pattern of behavioral outcome. These results may have implications for modeling interactions of genetic and environmental factors involved in schizophrenia, a disorder characterized by phenotypic heterogeneity, genetic predisposition, a developmental hippocampal abnormality, and vulnerability to environmental stress.

Two cystic fibrosis transmembrane conductance regulator mutations have different effects on both pulmonary phenotype and regulation of outwardly rectified chloride currents.

Cystic fibrosis (CF), a disorder of electrolyte transport manifest in the lungs, pancreas, sweat duct, and vas deferens, is caused by mutations in the CF transmembrane conductance regulator (CFTR). The CFTR protein has been shown to function as a cAMP-activated chloride channel and also regulates a separate protein, the outwardly rectifying chloride channel (ORCC). To determine the consequence of disease-producing mutations upon these functions, mutant CFTR was transiently expressed in Xenopus oocytes and in human airway epithelial cells lacking functional CFTR. Both G551D, a mutation that causes severe lung disease, and A455E, a mutation associated with mild lung disease, altered but did not abolish CFTR's function as a chloride channel in Xenopus oocytes. Airway epithelial cells transfected with CFTR bearing either A455E or G551D had levels of chloride conductance significantly greater than those of mock-transfected and lower than those of wild-type CFTR-transfected cells, as measured by chloride efflux. A combination of channel blockers and analysis of current-voltage relationships were used to dissect the contribution of CFTR and the ORCC to whole cell currents of transfected cells. While CFTR bearing either mutation could function as a chloride channel, only CFTR bearing A455E retained the function of regulating the ORCC. These results indicate that CF mutations can affect CFTR functions differently and suggest that severity of pulmonary disease may be more closely associated with the regulatory rather than chloride channel function of CFTR.

Effects of the environment on the electric conductivity of double-stranded DNA molecules

We present a theoretical analysis of the effects of the environment on charge transport in double-stranded synthetic poly(G)-poly(C) DNA molecules attached to two ideal leads. Coupling of the DNA to the environment results in two effects: (i) localization of carrier functions due to static disorder and (ii) phonon-induced scattering of the carriers between the localized states, resulting in hopping conductivity. A nonlinear Pauli master equation for populations of localized states is used to describe the hopping transport and calculate the electric current as a function of the applied bias. We demonstrate that, although the electronic gap in the density of states shrinks as the disorder increases, the voltage gap in the I-V characteristics becomes wider. A simple physical explanation of this effect is provided.

Molecular Genetic Basis of Opposite Gene by Environment Interactions in Reading Disability and Attention Deficit/Hyperactivity Disorder

The goal of this study is to better understand the genetic basis of Reading Disability (RD) and Attention Deficit Hyperactivity Disorder (ADHD) by examining molecular G x E interactions with parental education for each disorder. Research indicates that despite sharing genetic risk factors, RD and ADHD are influenced by different types of G x E interactions with parental education - a diathesis stress interaction in the case of ADHD and a bioecological interaction in RD. In order to resolve this apparent paradox, we conducted a preliminary study using behavioral genetic methods to test for G x E interactions in RD and the inattentive subtype of ADHD (ADHD-I) in the same sample of monozygotic and dizygotic Colorado Learning Disabilities Research Center same-sex twin pairs (DeFries et al., 1997), and our findings were consistent with the literature. We posited a genetic hypothesis for this opposite pattern of interactions, which suggests that only genes specific to each disorder enter into these opposite interactions, not the shared genes underlying their comorbidity. This study sought to further investigate this paradox using molecular genetics methods. We examined multiple candidate genes identified for RD or related language phenotypes and those identified for ADHD for G x E interactions with parental education. The specific aims of this study were as follows: 1) partition known risk alleles for RD and/or related language phenotypes and ADHD-I into those which are pleiotropic and non-pleiotropic by testing each risk allele for association with both RD and ADHD-I, 2) explore the main effects of parental education on both RD and ADHD-I, 3) address G-E correlations, and 4) conduct exploratory G x E interaction analyses in order to test the genetic hypothesis. Analyses suggested a number of pleiotropic genes that influence both RD and ADHD; however, results did not remain after correcting for multiple comparisons. Although exploratory G x E interaction findings were not significant after multiple comparison correction, results suggested a G x E interaction in the bioecological direction with KIAA0319, parental education, and ADHD-I. Given the limited power in the current study, replication of these findings with larger samples is necessary.