Hippocampus,delay discounting,and vicarious trial‐and‐error

In decision‐making, an immediate reward is usually preferred to a delayed reward, even if the latter is larger. We tested whether the hippocampus is necessary for this form of temporal discounting, and for vicarious trial‐and‐error at the decision point. Rats were trained on a recently developed, adjustable delay‐discounting task (Papale et al. (2012) Cogn Affect Behav Neurosci 12:513–526), which featured a choice between a small, nearly immediate reward, and a larger, delayed reward. Rats then received either hippocampus or sham lesions. Animals with hippocampus lesions adjusted the delay for the larger reward to a level similar to that of sham‐lesioned animals, suggesting a similar valuation capacity. However, the hippocampus lesion group spent significantly longer investigating the small and large rewards in the first part of the sessions, and were less sensitive to changes in the amount of reward in the large reward maze arm. Both sham‐ and hippocampus‐lesioned rats showed a greater amount of vicarious trial‐and‐error on trials in which the delay was adjusted. In a nonadjusting version of the delay discounting task, animals with hippocampus lesions showed more variability in their preference for a larger reward that was delayed by 10 s compared with sham‐lesioned animals. To verify the lesion behaviorally, rat were subsequently trained on a water maze task, and rats with hippocampus lesions were significantly impaired compared with sham‐lesioned animals. The findings on the delay discounting tasks suggest that damage to the hippocampus may impair the detection of reward magnitude. © 2014 Wiley Periodicals, Inc.     

Differential expression of protocadherin‐19, protocadherin‐17, and cadherin‐6 in adult zebrafish brain

Cell adhesion molecule cadherins play important roles in both development and maintenance of adult structures. Most studies on cadherin expression have been carried out in developing organisms, but information on cadherin distribution in adult vertebrate brains is limited. In this study we used in situ hybridization to examine mRNA expression of three cadherins, protocadherin‐19, protocadherin‐17, and cadherin‐6 in adult zebrafish brain. Each cadherin exhibits a distinct expression pattern in the fish brain, with protocadherin‐19 and protocadherin‐17 showing much wider and stronger expression than that of cadherin‐6. Both protocadherin‐19 and protocadherin‐17‐expressing cells occur throughout the brain, with strong expression in the ventromedial telencephalon, periventricular regions of the thalamus and anterior hypothalamus, stratum periventriculare of the optic tectum, dorsal tegmental nucleus, granular regions of the cerebellar body and valvula, and superficial layers of the facial and vagal lobes. Numerous sensory structures (e.g., auditory, gustatory, lateral line, olfactory, and visual nuclei) and motor nuclei (e.g., oculomotor, trochlear, trigeminal motor, abducens, and vagal motor nuclei) contain protocadherin‐19 and/or protocadherin‐17‐expressing cell. Expression of these two protocadherins is similar in the ventromedial telencephalon, thalamus, hypothalamus, facial, and vagal lobes, but substantially different in the dorsolateral telencephalon, intermediate layers of the optic tectum, and cerebellar valvula. In contrast to the two protocadherins, cadherin‐6 expression is much weaker and limited in the adult fish brain. J. Comp. Neurol. 523:1419–1442, 2015. © 2015 Wiley Periodicals, Inc.     

Perampanel,a selective,noncompetitive α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid receptor antagonist,as adjunctive therapy for refractory partial‐onset seizures: Interim results from phase III,extension study 307

Purpose: To evaluate safety, tolerability, and seizure outcome data during long‐term treatment with once‐daily adjunctive perampanel (up to 12 mg/day) in patients with refractory partial‐onset seizures. Methods: Study 307 was an extension study for patients completing the double‐blind phase of three pivotal phase III trials (studies 304, 305, and 306). The study consisted of two phases: an open‐label treatment phase (including a 16‐week blinded conversion period and a planned 256‐week maintenance period) and a 4‐week follow‐up phase. Patients were blindly titrated during the conversion period to their individual maximum tolerated dose (maximum 12 mg/day). Adverse events (AEs) were monitored throughout the study and seizure frequency recorded. The interim data cutoff date for analyses was December 1, 2010. Key Findings: In total, 1,218 patients were enrolled in the study. At the interim cutoff date, 1,186 patients were in the safety analysis set; 1,089 (91.8%) patients had >16 weeks of exposure to perampanel, 580 (48.9%) patients had >1 year of exposure, and 19 (1.6%) patients had >2 years of exposure. At the interim analysis, 840 (70.8%) patients remained on perampanel treatment. The large majority of patients (n = 1,084 [91%]) were titrated to 10 mg or 12 mg/day. Median (range) duration of exposure was 51.4 (1.1–128.1) weeks. Treatment‐emergent AEs were reported in 87.4% of patients. The most frequent were dizziness (43.9%), somnolence (20.2%), headache (16.7%), and fatigue (12.1%). Serious AEs were reported in 13.2% of patients. In the intent‐to‐treat analysis set (n = 1,207), the frequency of all seizures decreased over the first 26 weeks of perampanel treatment in patients with at least 26 weeks of exposure to perampanel (n = 1,006 [83.3%]); this reduction was maintained in patients with at least 1 year of exposure (n = 588 [48.7%]). The overall median percent changes in seizure frequency in patients included in each 13‐week interval of perampanel treatment were ?39.2% for weeks 14–26 (n = 1,114), ?46.5% for weeks 40–52 (n = 731), and ?58.1% for weeks 92–104 (n = 59). Overall responder rates in patients included in each 13‐week interval of perampanel treatment were 41.4% for weeks 14–26 (n = 1,114), 46.9% for weeks 40–52 (n = 731), and 62.7% for weeks 92–104 (n = 59). During the blinded conversion period, the reduction in seizure frequency in patients previously randomized to placebo (?42.4%, n = 369) was similar to that in patients previously randomized to perampanel (?41.5%, n = 817). Significance: Consistent with pivotal phase III trials, these interim results demonstrated that perampanel had a favorable tolerability profile in patients with refractory partial‐onset seizures over the longer term. The decrease in seizure frequency was consistent and maintained in those patients over at least 1 year of perampanel exposure.     

A randomized,double‐blind,placebo‐controlled,parallel‐group,enriched‐design study of nabiximols* (Sativex®), as add‐on therapy,in subjects with refractory spasticity caused by multiple sclerosis

Background: Spasticity is a disabling complication of multiple sclerosis, affecting many patients with the condition. We report the first Phase 3 placebo‐controlled study of an oral antispasticity agent to use an enriched study design. Methods: A 19‐week follow‐up, multicentre, double‐blind, randomized, placebo‐controlled, parallel‐group study in subjects with multiple sclerosis spasticity not fully relieved with current antispasticity therapy. Subjects were treated with nabiximols, as add‐on therapy, in a single‐blind manner for 4 weeks, after which those achieving an improvement in spasticity of ≥20% progressed to a 12‐week randomized, placebo‐controlled phase. Results: Of the 572 subjects enrolled, 272 achieved a ≥20% improvement after 4 weeks of single‐blind treatment, and 241 were randomized. The primary end‐point was the difference between treatments in the mean spasticity Numeric Rating Scale (NRS) in the randomized, controlled phase of the study. Intention‐to‐treat (ITT) analysis showed a highly significant difference in favour of nabiximols (P = 0.0002). Secondary end‐points of responder analysis, Spasm Frequency Score, Sleep Disturbance NRS Patient, Carer and Clinician Global Impression of Change were all significant in favour of nabiximols. Conclusions: The enriched study design provides a method of determining the efficacy and safety of nabiximols in a way that more closely reflects proposed clinical practice, by limiting exposure to those patients who are likely to benefit from it. Hence, the difference between active and placebo should be a reflection of efficacy and safety in the population intended for treatment.     

Assessment of idiopathic rapid‐eye‐movement sleep behavior disorder by transcranial sonography,olfactory function test,and FP‐CIT‐SPECT

Idiopathic rapid‐eye‐movement (REM) sleep behavior disorder (iRBD) has been suggested to be a risk factor for subsequent development of neurodegenerative disorders, especially Parkinson's disease (PD) and other α‐synucleinopathies. At present, it is not possible to predict whether or not an iRBD patient will eventually develop PD. Here, we report 5 iRBD patients who underwent a test battery comprising a neurological examination (including UPDRS rating), mini mental state examination testing, transcranial sonography, olfactory function testing, and presynaptic dopamine transporter imaging with FP‐CIT‐SPECT. Our preliminary data show the diverse pattern of individual combinations of pathological findings when a multimodal assessment approach is applied in this patient group. Large‐size longitudinal studies in iRBD patients are required to evaluate the usefulness of diagnostic tests to identify the subgroup of iRBD patients that is prone to develop PD. © 2007 Movement Disorder Society     

4‐hydroxy‐3‐methoxy‐acetophenone‐mediated long‐lasting memory recovery,hippocampal neuroprotection,and reduction of glial cell activation after transient global cerebral ischemia in rats

4‐Hydroxy‐3‐methoxy‐acetophenone (apocynin) is a naturally occurring methoxy‐substitute catechol that is isolated from the roots of Apocynin cannabinum (Canadian hemp) and Picrorhiza kurroa (Scrophulariaceae). It has been previously shown to have antioxidant and neuroprotective properties in several models of neurodegenerative disease, including cerebral ischemia. The present study investigates the effects of apocynin on transient global cerebral ischemia (TGCI)‐induced retrograde memory deficits in rats. The protective effects of apocynin on neurodegeneration and the glial response to TGCI are also evaluated. Rats received a single intraperitoneal injection of apocynin (5 mg/kg) 30 min before TGCI and were tested 7, 14, and 21 days later in the eight‐arm aversive radial maze (AvRM). After behavioral testing, the hippocampi were removed for histological evaluation. The present results confirm that TGCI causes memory impairment in the AvRM and that apocynin prevents these memory deficits and attenuates hippocampal neuronal death in a sustained way. Apocynin also decreases OX‐42 and glial fibrillary acidic protein immunoreactivity induced by TGCI. These findings support the potential role of apocynin in preventing neurodegeneration and cognitive impairments following TGCI in rats. The long‐term protective effects of apocynin may involve inhibition of the glial response. © 2015 Wiley Periodicals, Inc.     

A Retrospective,Long‐term,Third‐Party Follow‐up of Patients Considered for Spinal Cord Stimulation

The objective of this study was to follow up patients considered for spinal cord stimulation and assess outcomes and patient selection factors associated with outcome. A retrospective study of patients considered for spinal cord stimulation was performed. This included three groups: A) those who did not have a temporary trial of stimulation, B) those who did not go on to have long‐term stimulation after a trial, and C) those who did go on to have long‐term stimulation after a trial. Patient notes were obtained, a structured telephone interview conducted, and patients returned a questionnaire. VAS scores, percentage pain reduction reported, quality of life reports, Oswestry Disability Index and Hospital Anxiety and Depression Indices were recorded. Fifty‐two percent of patients who had long‐term stimulation reported 50% or greater pain reduction. In the subset of these patients with the diagnosis of failed back surgical syndrome, 51% reported 50% or greater pain reduction. Significant improvements in VAS, Oswestry Disability Index, and depression were reported pre and post long‐term stimulation. There were significant differences in the quality‐of‐life reports between the patients who received long‐term stimulation (who showed a positive outcome) and those who did not (who showed a negative outcome); 80% of patients receiving long‐term stimulation reported an improvement in their quality of life. Follow‐up of a cohort of patients receiving long‐term stimulation demonstrated some reduction of treatment efficacy. Use of a psychological interview aided patient selection, but no other factors showed a correlation with reported pain reduction. No serious adverse effects were demonstrated. A revision rate of 23.5% occured in long‐term stimulated patients. We conclude that spinal cord stimulation is an efficacious therapy which is not associated with serious side effects. There is some reduction in therapeutic efficacy over time. Patients deteriorate without treatment.     

Randomized, 8‐week,double‐blind,placebo‐controlled trial of vortioxetine in Japanese adults with major depressive disorder,followed by a 52‐week open‐label extension trial

Aim

Safety and efficacy of vortioxetine (5–20 mg/day) in Japanese patients with major depressive disorder were evaluated in two phase 3 studies consisting of a short‐term, 8‐week, placebo‐controlled, double‐blind study followed by a long‐term, 52‐week, open‐label extension study.

Methods

The primary end‐point of the short‐term study was change from baseline in Montgomery–Åsberg Depression Rating Scale (MADRS) total score at week 8. The primary objective of the extension study was vortioxetine's long‐term safety; efficacy end‐points included change in MADRS total score, Clinical Global Impression Scale (CGI)–Severity (S) score from the long‐term study baseline, and CGI–Improvement (CGI‐I) score over 52 weeks.

Results

Of the 366 randomized patients, 338 completed the short‐term study, and 119 patients continued into the extension study. Primary (analysis of covariance) and secondary (mixed model for repeated measurements) analyses in the short‐term study showed numerically greater, but not statistically significant, decreases in change in MADRS total score from baseline between the vortioxetine and placebo groups at week 8. In the long‐term study, 86.6% of patients reported at least one treatment‐emergent adverse event, with the most common being nasopharyngitis (40.3%) and nausea (21%). MADRS total score and CGI‐I and CGI‐S scores improved with continued vortioxetine treatment from baseline of the open‐label study to week 52.

Conclusion

Vortioxetine failed to meet significance versus placebo in the primary efficacy analysis at week 8 in the short‐term study. The extension trial indicated continued improvement of depressive symptoms from baseline of this study throughout the 52‐week treatment period. Vortioxetine treatment was safe and well tolerated in both studies.     

Multicenter,randomized, double‐blind,active comparator and placebo‐controlled trial of a corticotropin‐releasing factor receptor‐1 antagonist in generalized anxiety disorder

Background: Antagonism of corticotropin‐releasing factor (CRF) receptors has been hypothesized as a potential target for the development of novel anxiolytics. This study was designed to determine the safety and efficacy of pexacerfont, a selective CRF‐1 receptor antagonist, in the treatment of generalized anxiety disorder (GAD). Method: This was a multicenter, randomized, double‐blind, placebo‐controlled and active comparator trial. Two hundred and sixty patients were randomly assigned to pexacerfont 100 mg/day (after a 1 week loading dose of 300 mg/day), placebo or escitalopram 20 mg/day in a 2:2:1 ratio. The primary outcome was the mean change from baseline to end point (week 8) in the Hamilton Anxiety Scale total score. Results: Pexacerfont 100 mg/day did not separate from placebo on the primary outcome measure. The half‐powered active comparator arm, escitalopram 20 mg/day, demonstrated efficacy with significant separation from placebo at weeks 1, 2, 3, 6, and 8 (P<.02). Response rates for pexacerfont, placebo, and escitalopram were 42, 42, and 53%, respectively. Genetic and psychometric rating scale data was obtained in 175 randomized subjects. There was a significant association between a single nucleotide polymorphism (SNP) of the gene encoding plexin A2 (PLXNA2‐2016) with the HAM‐A psychic subscale score for the entire cohort at baseline (FDR‐adjusted P=.015). Conclusions: Pexacerfont did not demonstrate efficacy compared to placebo for the treatment of GAD. Whether these findings are generalizable to this class of agents remains to be determined. Our preliminary genetic finding of an association between a SNP for the gene encoding plexin A2 and an anxiety phenotype in this study merits further exploration. The trial was registered at clinicaltrials.gov (NCT00481325) before enrollment. Depression and Anxiety, 2010. © 2010 Wiley‐Liss, Inc.