Posttraumatic stress disorder (PTSD) is a chronic and disabling disorder, for which available pharmacotherapies have limited efficacy. The authors' previous proof-of-concept randomized controlled ...trial of single-dose intravenous ketamine infusion in individuals with PTSD showed significant and rapid PTSD symptom reduction 24 hours postinfusion. The present study is the first randomized controlled trial to test the efficacy and safety of repeated intravenous ketamine infusions for the treatment of chronic PTSD.
Individuals with chronic PTSD (N=30) were randomly assigned (1:1) to receive six infusions of ketamine (0.5 mg/kg) or midazolam (0.045 mg/kg) (psychoactive placebo control) over 2 consecutive weeks. Clinician-rated and self-report assessments were administered 24 hours after the first infusion and at weekly visits. The primary outcome measure was change in PTSD symptom severity, as assessed with the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5), from baseline to 2 weeks (after completion of all infusions). Secondary outcome measures included the Impact of Event Scale-Revised, the Montgomery-Åsberg Depression Rating Scale (MADRS), and side effect measures.
The ketamine group showed a significantly greater improvement in CAPS-5 and MADRS total scores than the midazolam group from baseline to week 2. At week 2, the mean CAPS-5 total score was 11.88 points (SE=3.96) lower in the ketamine group than in the midazolam group (d=1.13, 95% CI=0.36, 1.91). Sixty-seven percent of participants in the ketamine group were treatment responders, compared with 20% in the midazolam group. Among ketamine responders, the median time to loss of response was 27.5 days following the 2-week course of infusions. Ketamine infusions were well tolerated overall, without serious adverse events.
This randomized controlled trial provides the first evidence of efficacy of repeated ketamine infusions in reducing symptom severity in individuals with chronic PTSD. Further studies are warranted to understand ketamine's full potential as a treatment for chronic PTSD.
Preclinical studies point to the KCNQ2/3 potassium channel as a novel target for the treatment of depression and anhedonia, a reduced ability to experience pleasure. The authors conducted the first ...randomized placebo-controlled trial testing the effect of the KCNQ2/3 positive modulator ezogabine on reward circuit activity and clinical outcomes in patients with depression.
Depressed individuals (N=45) with elevated levels of anhedonia were assigned to a 5-week treatment period with ezogabine (900 mg/day; N=21) or placebo (N=24). Participants underwent functional MRI during a reward flanker task at baseline and following treatment. Clinical measures of depression and anhedonia were collected at weekly visits. The primary endpoint was the change from baseline to week 5 in ventral striatum activation during reward anticipation. Secondary endpoints included depression and anhedonia severity as measured using the Montgomery-Åsberg Depression Rating Scale (MADRS) and the Snaith-Hamilton Pleasure Scale (SHAPS), respectively.
The study did not meet its primary neuroimaging endpoint. Participants in the ezogabine group showed a numerical increase in ventral striatum response to reward anticipation following treatment compared with participants in the placebo group from baseline to week 5. Compared with placebo, ezogabine was associated with a significantly larger improvement in MADRS and SHAPS scores and other clinical endpoints. Ezogabine was well tolerated, and no serious adverse events occurred.
The study did not meet its primary neuroimaging endpoint, although the effect of treatment was significant on several secondary clinical endpoints. In aggregate, the findings may suggest that future studies of the KCNQ2/3 channel as a novel treatment target for depression and anhedonia are warranted.
Background The presence of multiple accessory pathways (MultAP) is described in structural heart disease (SHD) such as Ebstein's anomaly and cardiomyopathies. Structural defects can impact the ...tolerability of tachyarrhythmia and can complicate both medical management and ablation. In a large cohort of pediatric patients with and without SHD undergoing invasive electrophysiology study, we examined the prevalence of MultAP and the effect of both MultAP and SHD on ablation outcomes. Methods Accessory pathway number and location, presence of SHD, ablation success, and recurrence were analyzed in consecutive patients from our center over a 16-year period. Results In 1088 patients, 1228 pathways (36% retrograde only) were mapped to the right side (TV) in 18%, septum (S) in 39%, and left side (MV) in 43%. MultAP were present in 111 pts (10%), involving 250 distinct pathways. SHD tripled the risk of MultAP (26% SHD vs 8% no SHD, P < .001). Multivariable adjusted risk factors for MultAP included Ebstein's (OR 8.74.4-17.5, P < .001) and cardiomyopathy (OR 13.35.1-34.5, P < .001). Of 1306 ablation attempts, 94% were acutely successful with an 8% recurrence rate. Ablation success was affected by SHD (85% vs 95% for no SHD, P < .01) but not by MultAP (91% vs 94% for single, P = .24). Recurrence rate was higher for SHD (17% SHD vs 8% no SHD, P < .05) and MultAP (19% MultAP vs 8% single, P < .001). Conclusions MultAP are found in 10% of pediatric patients, and are more common in SHD compared to those with normal hearts. Both the presence of MultAP and SHD negatively influence ablation outcomes.
Impulsivity, describing action without foresight, is an important feature of several psychiatric diseases, suicidality and violent behaviour. The complex origins of impulsivity hinder identification ...of the genes influencing it and the diseases with which it is associated. Here we perform exon-focused sequencing of impulsive individuals in a founder population, targeting fourteen genes belonging to the serotonin and dopamine domain. A stop codon in HTR2B was identified that is common (minor allele frequency > 1%) but exclusive to Finnish people. Expression of the gene in the human brain was assessed, as well as the molecular functionality of the stop codon, which was associated with psychiatric diseases marked by impulsivity in both population and family-based analyses. Knockout of Htr2b increased impulsive behaviours in mice, indicative of predictive validity. Our study shows the potential for identifying and tracing effects of rare alleles in complex behavioural phenotypes using founder populations, and indicates a role for HTR2B in impulsivity.
Introduction: The incidence of appropriate and inappropriate discharges, indicators of system failure, and clinical implications of implantable cardioverter defibrillator (ICD) therapy in children ...and young adults with heart disease is poorly defined.
Methods and Results: In a retrospective study at a single medical center, a total of 90 ICD procedures were performed in 76 patients younger than age 30 years (median 16 years, range 1–30): 42% with congenital heart disease, 33% with primary electrical disease, 17% with hypertrophic cardiomyopathy, and 8% with idiopathic dilated cardiomyopathy. Indications for ICD included arrest or sustained ventricular tachycardia (n = 27), and combinations of syncope (n = 32), palpitations (n = 17), spontaneous ventricular arrhythmia (n = 40), inducible ventricular tachycardia (n = 36), or severe hypertrophic cardiomyopathy. Transvenous dual‐chamber ICDs were implanted in 29 patients. Subcutaneous arrays or epicardial patches were used in 9 patients. Over a median 2‐year follow‐up, 28% of patients received appropriate shocks for ventricular tachycardia (median 13 months to first shock) and 25% experienced inappropriate shocks for multiple causes (median 16 months). With multivariate analysis, growth strongly correlated with lead failure (odds ratio 73, 3.5–1530, P = 0.006). Complications occurred in 29 patients, including lead failure in 16 (21%), ICD “storm” with sequential shocks in 5, and infection in 2 patients. No deaths were attributable to ICD placement or subsequent device failure.
Conclusion: ICD therapy can effectively manage malignant arrhythmias in selected pediatric and congenital heart patients. Spurious shocks or ICD storm may increase morbidity and emphasize the need for concomitant medical and ablative therapy. ICD lead failure was relatively frequent in this population. (J Cardiovasc Electrophysiol, Vol. 15, pp. 72‐76, January 2004)
Ketamine has rapid and sustained antidepressant effects in patients with treatment-resistant depression (TRD). However, the underlying mechanisms of action are not well understood. There is ...increasing evidence that TRD is associated with a pro-inflammatory state and that ketamine may inhibit inflammatory processes. We thus investigated whole blood transcriptional profiles related to TRD and gene expression changes associated with treatment response to ketamine. Whole blood was collected at baseline (21 healthy controls HC, 26 patients with TRD) and then again in patients with TRD 24 hours following a single intravenous infusion of ketamine (0.5 mg/kg). We performed RNA-sequencing and analyzed (a) baseline transcriptional profiles between patients with TRD and HC, (b) responders vs. non-responders before ketamine treatment, and (c) gene expression signatures associated with clinical improvement. At baseline, patients with TRD compared to HC showed a gene expression signature indicative of interferon signaling pathway activation. Prior to ketamine administration, the metabotropic glutamate receptor gene GRM2 and the ionotropic glutamate receptor gene GRIN2D were upregulated in responders compared to non-responders. Response to ketamine was associated with a distinct transcriptional signature, however, we did not observe gene expression changes indicative of an anti-inflammatory effect. Future studies are needed to determine the role of the peripheral immune system in the antidepressant effect of ketamine.
Genetics of impulsive behaviour Bevilacqua, Laura; Goldman, David
Philosophical transactions of the Royal Society of London. Series B. Biological sciences,
04/2013, Letnik:
368, Številka:
1615
Journal Article
Recenzirano
Odprti dostop
Impulsivity, defined as the tendency to act without foresight, comprises a multitude of constructs and is associated with a variety of psychiatric disorders. Dissecting different aspects of impulsive ...behaviour and relating these to specific neurobiological circuits would improve our understanding of the etiology of complex behaviours for which impulsivity is key, and advance genetic studies in this behavioural domain. In this review, we will discuss the heritability of some impulsivity constructs and their possible use as endophenotypes (heritable, disease-associated intermediate phenotypes). Several functional genetic variants associated with impulsive behaviour have been identified by the candidate gene approach and re-sequencing, and whole genome strategies can be implemented for discovery of novel rare and common alleles influencing impulsivity. Via deep sequencing an uncommon HTR2B stop codon, common in one population, was discovered, with implications for understanding impulsive behaviour in both humans and rodents and for future gene discovery.
This study sought to determine the practical use of the recently introduced LINQ implantable loop recorder (LINQ-ILR) in a cohort of pediatric and adult congenital arrhythmia patients.
Correlating ...symptoms to a causative arrhythmia is a key aspect of diagnosis and management in clinical electrophysiology.
Retrospective review of clinical data, implantation indications, findings, and therapeutic decisions in patients who underwent LINQ-ILR implantation from April 1st, 2014 to January 30th, 2017 at Boston Children’s Hospital.
A total of 133 patients were included, of which 76 (57%) were male. The mean age at implantation was 15.7 ± 9.1 years with a duration of follow-up of 11.8 months. Congenital heart disease was present in 34 patients (26%), a confirmed genetic diagnosis in 50 (38%), and cardiomyopathy in 22 (26%), and the remainder were without a previous diagnosis. Syncope was the most common indication for LINQ-ILR implantation, occurring in 59 patients (44%). The median time to diagnosis was 4.5 months, occurring in 78 patients (59%). Cardiac device placement occurred in 17 patients (22%), a medication change in 9 (12%), electrophysiology study/ablation in 5 (6%), or LINQ-ILR explantation in 42 (54%). Infection or erosion occurred in 5 patients. Syncope was correlated with a diagnostic transmission (54% vs. 31%, p = 0.01).
The LINQ-ILR is an important diagnostic tool, providing useful data in more than one-half of patients in <6 months. Adverse events are low. Patient selection is critical and undiagnosed syncope represents an important presenting indication for which a LINQ-ILR implant should be considered.
Display omitted
The goal of this study was to identify factors associated with radiofrequency catheter ablation (RFCA) outcomes of intra-atrial re-entrant tachycardia (IART).
Radiofrequency catheter ablation of IART ...is difficult. The influence of patient and procedural factors and novel technologies on outcomes is unknown.
Acute and chronic RFCA outcomes were studied in patients with congenital heart disease and IART. Clinical status was measured using a multiaxis severity score. Multivariate analyses identified associations of clinical, procedural and technological factors with outcomes.
A total of 177 procedures were performed in 134 patients; 139 procedures (79%) resulted in RFCA of ≥1 IART circuit and 117 (66%) in RFCA of all targeted circuits. Multivariate analysis associated acute success with irrigated ablation and absence of atrial fibrillation. Twenty-two complications were noted, nine related to vascular access. Electroanatomic mapping failed to decrease procedure or fluoroscopy time. Improvement in clinical status occurred in most patients (severity score preablation: 6.2 ± 1.6, postablation: 3.0 ± 2.3, p < 0.0001). At mean follow-up of 25 ± 11 months, 42% of patients had IART recurrence and 28% required cardioversion. Six deaths occurred (1.8%/patient-year), and two patients underwent transplant. Chronic outcomes were associated with higher right atrial saturations, use of electroanatomic mapping, fewer IART circuits encountered and acute procedural success.
Improvement of acute RFCA outcomes was contemporaneous with introduction of novel technologies. Intra-atrial re-entrant tachycardia recurrence was common, and no effect on mortality was discerned, but most patients had effective palliation of symptoms. Chronic outcome predictors included the underlying disease severity, application of novel technologies and successful ablation of all targeted arrhythmia circuits.
Genetics of emotion Bevilacqua, Laura; Goldman, David
Trends in cognitive sciences,
09/2011, Letnik:
15, Številka:
9
Journal Article
Recenzirano
Odprti dostop
Emotion is critical to most aspects of human behavior, and individual differences in systems recruited to process emotional stimuli, expressed as variation in emotionality, are characteristic of ...several neuropsychiatric disorders. We examine the genetic origins of individual differences in emotion processing by focusing on functional variants at five genes: catechol- O -methyltransferase ( COMT ), serotonin transporter ( SLC6A4 ), neuropeptide Y ( NPY ), a glucocorticoid receptor-regulating co-chaperone of stress proteins ( FKBP5 ) and pituitary adenylate cyclase-activating polypeptide receptor (ADCYAP1R1). These represent a range of effects of genes on emotion as well as the variety of mechanisms and factors, such as stress, that modify these effects. The new genomic era of genome-wide association studies (GWAS) and deep sequencing may yield a wealth of new loci modulating emotion. The effects of these genes can be validated by neuroimaging, neuroendocrine and other studies accessing intermediate phenotypes, deepening our understanding of mechanisms of emotion and variation in emotionality.
PDF
