Trial of SAGE-217 in Patients with Major Depressive Disorder.

BACKGROUND: Altered neurotransmission of γ-aminobutyric acid (GABA) has been implicated in the pathogenesis of depression. Whether SAGE-217, an oral, positive allosteric modulator of GABA type A receptors, is effective and safe for the treatment of major depressive disorder is unknown. METHODS: In this double-blind, phase 2 trial, we enrolled patients with major depression and randomly assigned them in a 1:1 ratio to receive 30 mg of SAGE-217 or placebo once daily. The primary end point was the change from baseline to day 15 in the score on the 17-item Hamilton Depression Rating Scale (HAM-D; scores range from 0 to 52, with higher scores indicating more severe depression). Secondary efficacy end points, which were assessed on days 2 through 8 and on days 15, 21, 28, 35, and 42, included changes from baseline in scores on additional depression and anxiety scales, a reduction from baseline of more than 50% in the HAM-D score, a HAM-D score of 7 or lower, and a Clinical Global Impression of Improvement score of 1 (very much improved) or 2 (much improved) (on a scale of 1 to 7, with a score of 7 indicating that symptoms are very much worse). RESULTS: A total of 89 patients underwent randomization: 45 patients were assigned to the SAGE-217 group, and 44 to the placebo group. The mean baseline HAM-D score was 25.2 in the SAGE-217 group and 25.7 in the placebo group. The least-squares mean (±SE) change in the HAM-D score from baseline to day 15 was -17.4±1.3 points in the SAGE-217 group and -10.3±1.3 points in the placebo group (least-squares mean difference in change, -7.0 points; 95% confidence interval, -10.2 to -3.9; P<0.001). The differences in secondary end points were generally in the same direction as those of the primary end point. There were no serious adverse events. The most common adverse events in the SAGE-217 group were headache, dizziness, nausea, and somnolence. CONCLUSIONS: Administration of SAGE-217 daily for 14 days resulted in a reduction in depressive symptoms at day 15. Adverse events were more common in the SAGE-217 group than in the placebo group. Further trials are needed to determine the durability and safety of SAGE-217 in major depressive disorder and to compare SAGE-217 with available treatments. (Funded by Sage Therapeutics; ClinicalTrials.gov number, NCT03000530.).

A Pilot Randomized, Controlled, Double-Blind Trial of Bumetanide to Treat Neonatal Seizures.

OBJECTIVE: In the absence of controlled trials, treatment of neonatal seizures has changed minimally despite poor drug efficacy. We tested bumetanide added to phenobarbital to treat neonatal seizures in the first trial to include a standard-therapy control group. METHODS: A randomized, double-blind, dose-escalation design was employed. Neonates with postmenstrual age 33 to 44 weeks at risk of or with seizures were eligible. Subjects with electroencephalography (EEG)-confirmed seizures after ≥20 and <40mg/kg phenobarbital were randomized to receive additional phenobarbital with either placebo (control) or 0.1, 0.2, or 0.3mg/kg bumetanide (treatment). Continuous EEG monitoring data from ≥2 hours before to ≥48 hours after study drug administration (SDA) were analyzed for seizures. RESULTS: Subjects were randomized to treatment (n = 27) and control (n = 16) groups. Pharmacokinetics were highly variable among subjects and altered by hypothermia. The only statistically significant adverse event was diuresis in treated subjects (48% vs 13%, p = 0.02). One treated (4%) and 3 control subjects died (19%, p = 0.14). Among survivors, 2 of 26 treated subjects (8%) and 0 of 13 control subjects had hearing impairment, as did 1 nonrandomized subject. Total seizure burden varied widely, with much higher seizure burden in treatment versus control groups (median = 3.1 vs 1.2 min/h, p = 0.006). There was significantly greater reduction in seizure burden 0 to 4 hours and 2 to 4 hours post-SDA (both p < 0.01) compared with 2-hour baseline in treatment versus control groups with adjustment for seizure burden. INTERPRETATION: Although definitive proof of efficacy awaits an appropriately powered phase 3 trial, this randomized, controlled, multicenter trial demonstrated an additional reduction in seizure burden attributable to bumetanide over phenobarbital without increased serious adverse effects. Future trials of bumetanide and other drugs should include a control group and balance seizure severity. ANN NEUROL 2021;89:327-340.

Modulatory effect of long-term treatment with escitalopram and clonazepam on the expression of anxiety-related neuropeptides: neuromedin U, neuropeptide S and their receptors in the rat brain.

BACKGROUND: Newly identified multifunctional peptidergic modulators of stress responses: neuromedin U (NMU) and neuropeptide S (NPS) are involved in the wide spectrum of brain functions. However, there are no reports dealing with potential molecular relationships between the action of diverse anxiolytic or antidepressant drugs and NMU and NPS signaling in the brain. The present work was therefore focused on local expression of the aforementioned stress-related neuropeptides in the rat brain after long-term treatment with escitalopram and clonazepam. METHODS: Studies were carried out on adult, male Sprague-Dawley rats that were divided into 3 groups: animals injected with saline (control) and experimental individuals treated with escitalopram (at single dose 5 mg/kg daily), and clonazepam (at single dose 0.5 mg/kg). All individuals were sacrificed under anaesthesia and the whole brain excised. Total mRNA was isolated from homogenized samples of amygdala, hippocampus, hypothalamus, thalamus, cerebellum and brainstem. Real time-PCR method was used for estimation of related NPS, NPS receptor (NPSR), NMU, NMU and receptor 2 (NMUR2) mRNA expression. The whole brains were also sliced for general immunohistochemical assessment of the neuropeptides expression. RESULTS: Chronic administration of clonazepam resulted in an increase of NMU mRNA expression and formation of NMU-expressing fibers in the amygdala, while escitalopram produced a significant decrease in NPSR mRNA level in hypothalamus. Long-term escitalopram administration affects the local expression of examined neuropeptides mRNA in a varied manner depending on the brain structure. CONCLUSIONS: Pharmacological effects of escitalopram may be connected with local at least partially NPSR-related alterations in the NPS/NMU/NMUR2 gene expression at the level selected rat brain regions. A novel alternative mode of SSRI action can be therefore cautiously proposed.

Oxytetracycline induces anxiety-like behavior in adult zebrafish.

Oxytetracycline (OTC) is one of the broad-spectrum antibiotics widely used for the treatment of fish-farm infection. Considering that behavior is directly related to reproduction, individual fitness, and survival, it is important to evaluate the impact of antibiotics on the behavioral repertoire in fish. Zebrafish (Danio rerio) presents a well-described behavioral repertoire to reliably demonstrate complex responses to chemical compound exposure. This work aims to identify the role of OTC in comprehensive behavioral parameters and whole-body cortisol levels in adult zebrafish. Here we report that OTC exposure (10, 20, and 100 mg/L) induces an anxiogenic-like phenotype in the novel tank test. OTC exposure also changes the behavior of social interaction with a shoal of unknown zebrafish - characterized as a stimulus group. Zebrafish exposed to OTC (10 mg/L) remains a longer period in the stimulus zone when compared to the control group. Clonazepam (0.006 mg/L) was able to reverse anxiogenic-like behavior and the changes in social behavior induced by OTC. We also demonstrated that cortisol levels were significantly decreased after exposure to OTC (10, 20, and 100 mg/L), which were not reversed by clonazepam. These findings highlight the growing utility of zebrafish as a model to understand the impact of antibiotics on behavior and their underlying mechanisms.

West Nile Virus Neuroinvasive Disease Accelerating Probable Dementia With Lewy Bodies.

We describe a case of dementia with Lewy bodies immediately following encephalitis due to West Nile virus (WNV). The patient had rapid eye movement-sleep behavior disorder and constipation before the onset of encephalitis, which suggests that he would have ultimately developed dementia with Lewy bodies even without WNV infection. Our case illustrates the interactions between α-synuclein and WNV, as observed in mouse models, wherein synuclein expression augments after WNV infection and protects neurons against the virus.

Age of Diagnosis and Comorbid PLMD Predict Poor Response of REM Behavior Disorder to Clonazepam.

Previous studies have shown the therapeutic effects of clonazepam for rapid eye movement sleep behavior disorder (RBD), but they had several limitations such as the lack of clear definition of treatment outcomes and little information about adjuvant therapy. The aims of this study were to evaluate the treatment outcomes with clonazepam and to explore possible determinants of treatment response. We performed a retrospective medical chart review of 171 patients with RBD. All the participants underwent overnight polysomnography and completed questionnaires. The positive treatment response was defined as the absence of disruptive behaviors causing sleep-related injuries during the last year of follow-up. Among the 171 patients presented with disruptive behaviors, 155 (90.6%) experienced positive treatment responses. Of the responders, 18 (11.6%) received adjunctive medication due to insufficient therapeutic effect of clonazepam monotherapy. After adjusted analysis, an earlier age of diagnosis (odds ratio [OR] = 0.74, 95% confidence interval [CI] = 0.64-0.86, P < .001) and comorbid periodic limb movement during sleep (OR = 4.96, 95% CI = 1.05-23.33, P = .043) were related to poor treatment response. Clinicians should recognize the predictors of poor treatment response and consider combination therapy for better prevention of sleep-related injuries in those who show unsatisfactory responses to clonazepam monotherapy.

Effect of Curcuma zedoaria hydro-alcoholic extract on learning, memory deficits and oxidative damage of brain tissue following seizures induced by pentylenetetrazole in rat.

BACKGROUND: Previous studies have shown that seizures can cause cognitive disorders. On the other hand, the Curcuma zedoaria (CZ) has beneficial effects on the nervous system. However, there is little information on the possible effects of the CZ extract on seizures. The aim of this study was to investigate the possible effects of CZ extract on cognitive impairment and oxidative stress induced by epilepsy in rats. METHODS: Rats were randomly divided into different groups. In all rats (except the sham group), kindling was performed by intraperitoneal injection of pentylenetetrazol (PTZ) at a dose of 35 mg/kg every 48 h for 14 days. Positive group received 2 mg/kg diazepam + PTZ; treatment groups received 100, 200 or 400 mg/kg CZ extract + PTZ; and one group received 0.5 mg/kg flumazenil and CZ extract + PTZ. Shuttle box and Morris Water Maze tests were used to measure memory and learning. On the last day of treatments PTZ injection was at dose of 60 mg/kg, tonic seizure threshold and mortality rate were recorded in each group. After deep anesthesia, blood was drawn from the rats' hearts and the hippocampus of all rats was removed. RESULTS: Statistical analysis of the data showed that the CZ extract significantly increased the tonic seizure threshold and reduced the pentylenetetrazol-induced mortality and the extract dose of 400 mg/kg was selected as the most effective dose compared to the other doses. It was also found that flumazenil (a GABAA receptor antagonist) reduced the tonic seizure threshold compared to the effective dose of the extract. The results of shuttle box and Morris water maze behavioral tests showed that memory and learning decreased in the negative control group and the CZ extract treatment improved memory and learning in rats. The CZ extract also increased antioxidant capacity, decreased MDA and NO in the brain and serum of pre-treated groups in compared to the negative control group. CONCLUSION: It is concluded that the CZ extract has beneficial effects on learning and memory impairment in PTZ-induced epilepsy model, which has been associated with antioxidant effects in the brain or possibly exerts its effects through the GABAergic system.

Neurocovid: Pharmacological Recommendations for Delirium Associated With COVID-19.

BACKGROUND: The pandemic of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has emerged as one of the biggest health threats of our generation. A significant portion of patients are presenting with delirium and neuropsychiatric sequelae of the disease. Unique examination findings and responses to treatment have been identified. OBJECTIVE: In this article, we seek to provide pharmacologic and treatment recommendations specific to delirium in patients with COVID-19. METHODS: We performed a literature search reviewing the neuropsychiatric complications and treatments in prior coronavirus epidemics including Middle Eastern respiratory syndrome and severe acute respiratory syndrome coronaviruses, as well as the emerging literature regarding COVID-19. We also convened a work group of consultation-liaison psychiatrists actively managing patients with COVID-19 in our hospital. Finally, we synthesized these findings to provide preliminary pharmacologic recommendations for treating delirium in these patients. RESULTS: Delirium is frequently found in patients who test positive for COVID-19, even in the absence of respiratory symptoms. There appears to be a higher rate of agitation, myoclonus, abulia, and alogia. No data are currently available on the treatment of delirium in patients with COVID-19. Extrapolating from general delirium treatment, Middle Eastern respiratory syndrome/severe acute respiratory syndrome case reports, and our experience, preliminary recommendations for pharmacologic management have been assembled. CONCLUSIONS: COVID-19 is associated with neuropsychiatric symptoms. Low-potency neuroleptics and alpha-2 adrenergic agents may be especially useful in this setting. Further research into the pathophysiology of COVID-19 will be key in developing more targeted treatment guidelines.

Treatment of essential tremor: current status.

Essential tremor is the most common cause of tremor involving upper limbs, head and voice. The first line of treatment for limb tremor is pharmacotherapy with propranolol or primidone. However, these two drugs reduce the tremor severity by only half. In medication refractory and functionally disabling tremor, alternative forms of therapy need to be considered. Botulinum toxin injections are likely efficacious for limb, voice and head tremor but are associated with side effects. Surgical interventions include deep brain stimulation; magnetic resonance-guided focused ultrasound and thalamotomy for unilateral and deep brain stimulation for bilateral procedures. Recent consensus classification for essential tremor has included a new subgroup, 'Essential tremor plus', who have associated subtle neurological 'soft signs', such as dystonic posturing of limbs and may require a different treatment approach. In this review, we have addressed the current management of essential tremor with regard to different anatomical locations of tremor as well as different modalities of treatment.

Efficacy of yokukansan compared with clonazepam for rapid eye movement sleep behaviour disorder: a preliminary retrospective study.

AIM: Rapid eye movement sleep behaviour disorder (RBD) is characterized by abnormal behaviours accordant with nightmares during rapid eye movement sleep and is considered a prodromal marker of dementia with Lewy body. Most common in the elderly population, RBD is generally treated with clonazepam (CZP), a long-term acting benzodiazepine antiepileptic. As such, alternative drugs for RBD are urgently needed to minimize the adverse effects peculiar to benzodiazepines. The efficacy of yokukansan (YKS), a traditional Japanese herbal medicine, on RBD was initially reported by Shinno et al. in 2008. However, no study has compared YKS with CZP. Therefore, this study aimed to clarify the possibility of using YKS as an alternative to CZP. METHODS: This was a retrospective cohort study conducted at Jikei University Affiliated Hospital. The subjects were selected from 36 outpatients who had been diagnosed with RBD based on the International Classification of Sleep Disorders, third edition. Of the 23 who met the inclusion criteria but not the exclusion criteria, 11 were treated with YKS monotherapy, and 12 were treated with CZP monotherapy. The primary outcome was the total score on the Japanese version of the Rapid Eye Movement Sleep Behaviour Disorder Questionnaire (RBDQ-JP), and the secondary outcomes were the scores from the eight-item Short-Form Health Survey and factors 1 and 2 of the RBDQ-JP. RESULTS: The mean total RBDQ-JP score significantly improved from 52.5 to 21.7 (P = 0.002) after treatment with YKS (mean dosage: 3.0 g/day), which was similar to the change after CZP treatment (from 43.8 to 21.3). On RBDQ-JP factor 1 (dream content), the mean score on five of six items significantly improved after treatment with YKS. There was no significant change in Short-Form Health Survey scores after treatment with either drug. Potassium concentrations were within the normal range in patients treated with YKS. CONCLUSIONS: The present results suggest that a small amount of YKS may be an alternative to CZP for RBD, without remarkable adverse events. Further study is needed to prospectively clarify the efficacy and safety of YKS in more detail.

Pediatric Catatonia: A Case Series-Based Review of Presentation, Evaluation, and Management.

BACKGROUND: Pediatric catatonia is believed to be a rare condition, but challenges in recognition and variability in presentation may lead to underdiagnosis. Early identification and effective treatment of pediatric catatonia is critical given the significant morbidity and mortality associated with the condition. Given the widespread shortage of child and adolescent psychiatrists, at times consultation-liaison (C-L) psychiatrists without child training may be the frontline specialty providers asked to guide treatment of these pediatric patients. OBJECTIVE: To review the literature on pediatric catatonia using clinical cases to illustrate unique aspects of its presentation, evaluation, and management. METHODS: We describe the presentation and management of 6 adolescents with catatonia on an inpatient pediatric service at a general hospital and use these cases as a focal point for a review of the literature. CONCLUSION: Pediatric catatonia is a potentially lethal disease entity that can be effectively treated if accurately identified early in its course. Psychiatrists working in a C-L setting may encounter this syndrome and should be aware of its presentation, evaluation, and management.

Role of ß2/3-specific GABA-A receptor isoforms in the development of hippocampus kindling epileptogenesis.

OBJECTIVE: Subunit-specific positive allosteric modulators (PAMs) of gamma-aminobutyric acid-A (GABA-A) receptors are commonly used to uncover the role of GABA-A receptor isoforms in brain function. Recently, we have designed novel PAMs selective for ß2/3-subunit containing GABA-A receptors (ß2/3-selective PAMs) that are nonbenzodiazepine site-mediated and do not show an α-subunit isoform selectivity, yet exhibit anxiolytic efficacy with reduced potential for sedation, cognitive impairment, and tolerance. In this study, we used three novel ß2/3-selective PAMs (2-261, 2-262, and 10029) with differential ß2/3-subunit potency to identify the role of ß2/3-selective receptor isoforms in limbic epileptogenesis. METHODS: Experimental epileptogenesis was induced in mice by daily hippocampus stimulations until each mouse showed generalized (stage 5) seizures. Patch-clamp electrophysiology was used to record GABA-gated currents. Brain levels of ß2/3-selective PAMs were determined for mechanistic correlations. RESULTS: Treatment with the ß2/3-selective PAMs 2-261 (30mg/kg), 2-262 (10mg/kg), and 10029 (30mg/kg), 30min prior to stimulations, significantly suppressed the rate of development of kindled seizure activity without affecting the afterdischarge (AD) signal, indicating their disease-modifying activity. The ß2/3-selective agents suppressed chemical epileptogenesis in the pentylenetetrazol model. Test doses of these agents were devoid of acute antiseizure activity in the kindling model. CONCLUSION: These findings demonstrate that ß2/3-selective PAMs can moderately retard experimental epileptogenesis, indicating the protective role of ß2/3-subunit GABA-A receptor isoforms in the development of epilepsy.

Autistic-like behaviour in Scn1a+/- mice and rescue by enhanced GABA-mediated neurotransmission.

Haploinsufficiency of the SCN1A gene encoding voltage-gated sodium channel Na(V)1.1 causes Dravet's syndrome, a childhood neuropsychiatric disorder including recurrent intractable seizures, cognitive deficit and autism-spectrum behaviours. The neural mechanisms responsible for cognitive deficit and autism-spectrum behaviours in Dravet's syndrome are poorly understood. Here we report that mice with Scn1a haploinsufficiency exhibit hyperactivity, stereotyped behaviours, social interaction deficits and impaired context-dependent spatial memory. Olfactory sensitivity is retained, but novel food odours and social odours are aversive to Scn1a(+/-) mice. GABAergic neurotransmission is specifically impaired by this mutation, and selective deletion of Na(V)1.1 channels in forebrain interneurons is sufficient to cause these behavioural and cognitive impairments. Remarkably, treatment with low-dose clonazepam, a positive allosteric modulator of GABA(A) receptors, completely rescued the abnormal social behaviours and deficits in fear memory in the mouse model of Dravet's syndrome, demonstrating that they are caused by impaired GABAergic neurotransmission and not by neuronal damage from recurrent seizures. These results demonstrate a critical role for Na(V)1.1 channels in neuropsychiatric functions and provide a potential therapeutic strategy for cognitive deficit and autism-spectrum behaviours in Dravet's syndrome.

Benzodiazepines for antipsychotic-induced tardive dyskinesia.

BACKGROUND: Tardive dyskinesia (TD) is a disfiguring movement disorder, often of the orofacial region, frequently caused by using antipsychotic drugs. A wide range of strategies have been used to help manage TD, and for those who are unable to have their antipsychotic medication stopped or substantially changed, the benzodiazepine group of drugs have been suggested as a useful adjunctive treatment. However, benzodiazepines are very addictive. OBJECTIVES: To determine the effects of benzodiazepines for antipsychotic-induced tardive dyskinesia in people with schizophrenia, schizoaffective disorder, or other chronic mental illnesses. SEARCH METHODS: On 17 July 2015 and 26 April 2017, we searched the Cochrane Schizophrenia Group's Study-Based Register of Trials (including trial registers), inspected references of all identified studies for further trials and contacted authors of each included trial for additional information. SELECTION CRITERIA: We included all randomised controlled trials (RCTs) focusing on people with schizophrenia (or other chronic mental illnesses) and antipsychotic-induced TD that compared benzodiazepines with placebo, no intervention, or any other intervention for the treatment of TD. DATA COLLECTION AND ANALYSIS: We independently extracted data from the included studies and ensured that they were reliably selected, and quality assessed. For homogenous dichotomous data, we calculated random effects, risk ratio (RR), and 95% confidence intervals (CI). We synthesised continuous data from valid scales using mean differences (MD). For continuous outcomes, we preferred endpoint data to change data. We assumed that people who left early had no improvement. MAIN RESULTS: The review now includes four trials (total 75 people, one additional trial since 2006, 21 people) randomising inpatients and outpatients in China and the USA. Risk of bias was mostly unclear as reporting was poor. We are uncertain about all the effects as all evidence was graded at very low quality. We found no significant difference between benzodiazepines and placebo for the outcome of 'no clinically important improvement in TD' (2 RCTs, 32 people, RR 1.12, 95% CI 0.60 to 2.09, very low quality evidence). Significantly fewer participants allocated to clonazepam compared with phenobarbital (as active placebo) experienced no clinically important improvement (RR 0.44, 95% CI 0.20 to 0.96, 1 RCT, 21 people, very low quality evidence). For the outcome 'deterioration of TD symptoms,' we found no clear difference between benzodiazepines and placebo (2 RCTs, 30 people, RR 1.48, 95% CI 0.22 to 9.82, very low quality evidence). All 10 participants allocated to benzodiazepines experienced any adverse event compared with 7/11 allocated to phenobarbital (RR 1.53, 95% CI 0.97 to 2.41, 1 RCT, 21 people, very low quality evidence). There was no clear difference in the incidence of participants leaving the study early for benzodiazepines compared with placebo (3 RCTs, 56 people, RR 2.73, 95% CI 0.15 to 48.04, very low quality evidence) or compared with phenobarbital (as active placebo) (no events, 1 RCT, 21 people, very low quality evidence). No trials reported on social confidence, social inclusion, social networks, or personalised quality of life, which are outcomes designated important by patients. No trials comparing benzodiazepines with placebo or treatment as usual reported on adverse effects. AUTHORS' CONCLUSIONS: There is only evidence of very low quality from a few small and poorly reported trials on the effect of benzodiazepines as an adjunctive treatment for antipsychotic-induced TD. These inconclusive results mean routine clinical use is not indicated and these treatments remain experimental. New and better trials are indicated in this under-researched area; however, as benzodiazepines are addictive, we feel that other techniques or medications should be adequately evaluated before benzodiazepines are chosen.

Burning mouth syndrome: a systematic review of treatments.

Burning mouth syndrome (BMS) is a chronic oral pain syndrome that primarily affects peri- and postmenopausal women. It is characterized by oral mucosal burning and may be associated with dysgeusia, paresthesia, dysesthesia, and xerostomia. The etiology of the disease process is unknown, but is thought to be neuropathic in origin. The goal of this systematic review was to assess the efficacy of the various treatments for BMS. Literature searches were conducted through PubMed, Web of Science, and Cochrane Library databases, which identified 22 randomized controlled trials. Eight studies examined alpha-lipoic acid (ALA), three clonazepam, three psychotherapy, and two capsaicin, which all showed modest evidence of potentially decreasing pain/burning. Gabapentin was seen in one study to work alone and synergistically with ALA. Other treatments included vitamins, benzydamine hydrochloride, bupivacaine, Catuama, olive oil, trazodone, urea, and Hypericum perforatum. Of these other treatments, Catuama and bupivacaine were the only ones with significant positive results in symptom improvement. ALA, topical clonazepam, gabapentin, and psychotherapy may provide modest relief of pain in BMS. Gabapentin may also boost the effect of ALA. Capsaicin is limited by its side effects. Catuama showed potential for benefit. Future studies with standardized methodology and outcomes containing more patients are needed.

Short-term treatment with flumazenil restores long-term object memory in a mouse model of Down syndrome.

Down syndrome (DS) is a common genetic cause of intellectual disability yet no pro-cognitive drug therapies are approved for human use. Mechanistic studies in a mouse model of DS (Ts65Dn mice) demonstrate that impaired cognitive function is due to excessive neuronal inhibitory tone. These deficits are normalized by chronic, short-term low doses of GABAA receptor (GABAAR) antagonists in adult animals, but none of the compounds investigated are approved for human use. We explored the therapeutic potential of flumazenil (FLUM), a GABAAR antagonist working at the benzodiazepine binding site that has FDA approval. Long-term memory was assessed by the Novel Object Recognition (NOR) testing in Ts65Dn mice after acute or short-term chronic treatment with FLUM. Short-term, low, chronic dose regimens of FLUM elicit long-lasting (>1week) normalization of cognitive function in both young and aged mice. FLUM at low dosages produces long lasting cognitive improvements and has the potential of fulfilling an unmet therapeutic need in DS.

REM Sleep Behavior Disorder in Parkinson's Disease and Other Synucleinopathies.

Rapid eye movement sleep behavior disorder is characterized by dream enactment and complex motor behaviors during rapid eye movement sleep and rapid eye movement sleep atonia loss (rapid eye movement sleep without atonia) during polysomnography. Rapid eye movement sleep behavior disorder may be idiopathic or symptomatic and in both settings is highly associated with synucleinopathy neurodegeneration, especially Parkinson's disease, dementia with Lewy bodies, multiple system atrophy, and pure autonomic failure. Rapid eye movement sleep behavior disorder frequently manifests years to decades prior to overt motor, cognitive, or autonomic impairments as the presenting manifestation of synucleinopathy, along with other subtler prodromal "soft" signs of hyposmia, constipation, and orthostatic hypotension. Between 35% and 91.9% of patients initially diagnosed with idiopathic rapid eye movement sleep behavior disorder at a sleep center later develop a defined neurodegenerative disease. Less is known about the long-term prognosis of community-dwelling younger patients, especially women, and rapid eye movement sleep behavior disorder associated with antidepressant medications. Patients with rapid eye movement sleep behavior disorder are frequently prone to sleep-related injuries and should be treated to prevent injury with either melatonin 3-12 mg or clonazepam 0.5-2.0 mg to limit injury potential. Further evidence-based studies about rapid eye movement sleep behavior disorder are greatly needed, both to enable accurate prognostic prediction of end synucleinopathy phenotypes for individual patients and to support the application of symptomatic and neuroprotective therapies. Rapid eye movement sleep behavior disorder as a prodromal synucleinopathy represents a defined time point at which neuroprotective therapies could potentially be applied for the prevention of Parkinson's disease, dementia with Lewy bodies, multiple system atrophy, and pure autonomic failure. © 2017 International Parkinson and Movement Disorder Society.

A 6-Year Posttreatment Follow-up of Panic Disorder Patients: Treatment With Clonazepam Predicts Lower Recurrence Than Treatment With Paroxetine.

BACKGROUND: The aim of this study was to identify factors associated with relapse in panic disorder (PD). METHODS: This was an observational study conducted in the outpatient clinic of a psychiatric hospital in Rio de Janeiro, Brazil. In a previous study, 120 patients diagnosed as having PD according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria were randomized to receive clonazepam or paroxetine. After 3 years, treatment was discontinued in patients who had achieved remission. These subjects were included in the current study and were followed up for 6 years. The follow-up assessments were made at 1, 2, 3, 5, and 6 years after treatment discontinuation. Assessment included the number of panic attacks per month, Clinical Global Impression-Severity, and other measures. Patients who had initiated psychotherapy or pharmacological treatment because of PD symptoms or who had Clinical Global Impression-Severity scores greater than 1 or panic attacks in the month preceding the assessment were considered relapse cases. Data were collected from January 2003 to August 2012. RESULTS: Eighty-five patients completed the follow-up. Cumulative relapse rates were 50% (n = 33) at 1 year and 89.4% (n = 76) at 6 years. One-year relapse rates were lower in patients previously treated with clonazepam (P = 0.001) compared with those treated with paroxetine. Low 6-year relapse rates were associated with high Hamilton Anxiety Rating Scale scores before treatment (P = 0.016) and previous treatment with clonazepam. CONCLUSIONS: Relapse is a frequent problem in PD, and long-term treatment does not protect these patients in the long run. Treatment with clonazepam predicts lower relapse when compared with paroxetine.

Amisulpride Augmentation in Acute Catatonia.

Benzodiazepines are the first-line treatment of catatonia, but a substantial number of patients do not respond to them. Amisulpride is one of the atypical antipsychotic that has been effective for negative symptoms of schizophrenia. We examined the effect of augmentation of oral low doses of amisulpride with lorazepam on resolution of catatonic symptoms. Fifteen patients with catatonia were treated with a combination of oral lorazepam (2-4 mg) with amisulpride (100 mg). Catatonic symptoms were rated using the Bush Francis Catatonia Rating Scale at the baseline and daily thereafter. There was complete resolution of catatonic symptoms on the third day in all patients. There was significant reduction of the total Bush Francis Catatonia Rating Scale score over time (F = 181.38, P < 0.001) with a strong effect size (partial η = 0.96). Augmentation of lorazepam with low-dose amisulpride can be a reliable strategy for management of catatonia.