A cell-penetrant peptide blocking C9ORF72-repeat RNA nuclear export reduces the neurotoxic effects of dipeptide repeat proteins.

Hexanucleotide repeat expansions in C9ORF72 are the most common genetic cause of familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Studies have shown that the hexanucleotide expansions cause the noncanonical translation of C9ORF72 transcripts into neurotoxic dipeptide repeat proteins (DPRs) that contribute to neurodegeneration. We show that a cell-penetrant peptide blocked the nuclear export of C9ORF72-repeat transcripts in HEK293T cells by competing with the interaction between SR-rich splicing factor 1 (SRSF1) and nuclear export factor 1 (NXF1). The cell-penetrant peptide also blocked the translation of toxic DPRs in neurons differentiated from induced neural progenitor cells (iNPCs), which were derived from individuals carrying C9ORF72-linked ALS mutations. This peptide also increased survival of iNPC-differentiated C9ORF72-ALS motor neurons cocultured with astrocytes. Oral administration of the cell-penetrant peptide reduced DPR translation and rescued locomotor deficits in a Drosophila model of mutant C9ORF72-mediated ALS/FTD. Intrathecal injection of this peptide into the brains of ALS/FTD mice carrying a C9ORF72 mutation resulted in reduced expression of DPRs in mouse brains. These findings demonstrate that disrupting the production of DPRs in cellular and animal models of ALS/FTD might be a strategy to ameliorate neurodegeneration in these diseases.

Impact of Gabapentin Adjunct use with Benzodiazepines for the Treatment of Alcohol Withdrawal in a Psychiatric Hospital.

Introduction: Benzodiazepines are currently the gold standard for treatment of alcohol withdrawal. Gabapentin has growing evidence to support its use in the treatment of alcohol use disorder, however there is limited evidence regarding its role in the treatment of alcohol withdrawal. The purpose of this study was to determine if adjunctive gabapentin reduces the need for benzodiazepine (BZD) administration during alcohol withdrawal. Methods: This was a retrospective single-center cohort study. Patients were included if they were 18-89 years old, had an underlying alcohol use disorder, and were initiated on the Clinical Institute Withdrawal Assessment of Alcohol Scale, Revised (CIWA-Ar) protocol with or without scheduled gabapentin. They were excluded if they had a BZD use disorder, were on concomitant anti-epileptics, as-needed gabapentin, or BZDs outside the CIWA-Ar protocol. Results: A total of 129 patients met inclusion criteria (n = 63 gabapentin group and 66 non-gabapentin group). There was a significant difference in as-needed BZD requirements, with the gabapentin group requiring a higher number of as-needed BZDs in the initial 72 hours of treatment (gabapentin 6 [IQR 0.5-10] non-gabapentin 2 [IQR 0-4]; p = 0.01) and overall (gabapentin 6 [IQR 0.5-10] vs. non-gabapentin 2 [IQR 0-5.5]; p = 0.01). The gabapentin group also had higher maximum CIWA-Ar scores in the initial 72 hours of treatment, and higher anxiety item scores in the initial 48 hours. Conclusion: Gabapentin was not shown to reduce as-needed BZD requirements in patients with a diagnosis of alcohol use disorder admitted for alcohol withdrawal.

Treatment of Catatonia With Ultrabrief Right Unilateral Electroconvulsive Therapy: A Case Series.

Catatonia is a syndrome heterogeneous with regard to presentation and etiology. Electroconvulsive therapy (ECT) remains the first-line treatment for catatonia. Literature review reveals only a few published case reports on the use of right unilateral (RUL) ECT in catatonia, 1 case report on ultrabrief RUL ECT, and an absence of evidence on the relative effectiveness and tolerability of RUL versus bilateral ECT in treating catatonia. In contrast, there are multiple reports in the literature of robustly dosed bilateral ECT, often administered on consecutive days. Reasons for choosing this intervention over the better-tolerated RUL treatment include assumptions about its relative speed and/or breadth of efficacy. Here we present a case series of 13 catatonic patients treated in an academic center over the course of the last 3 years. Our experience suggests that ultrabrief RUL ECT can rapidly and effectively treat catatonia from diverse etiologies.

Current treatment strategies for clozapine-induced sialorrhea.

OBJECTIVE: To provide an understanding of the underlying pathophysiology and current treatment options for clozapine-induced sialorrhea. DATA SOURCES: Literature was retrieved through MEDLINE (1977-February 2011) using the key search terms clozapine, sialorrhea, hypersalivation, drooling, and treatment. In addition, reference citations from identified publications were reviewed. STUDY SELECTION AND DATA EXTRACTION: All articles published in English identified from the data source were evaluated and included in the review. DATA SYNTHESIS: Sialorrhea is a common and disabling adverse effect of clozapine use. Current treatment options include topical and oral antimuscarinic medications and α-adrenergic agents. New areas of investigation include glycopyrrolate, botulinum toxin, and substitute benzamide derivatives. Thirteen clinical trials (2 retrospective, 5 open-label, 6 double-blind) and 13 case reports were reviewed. Overall, there are weak data on use of antimuscarinic agents, consisting mostly of small open-label or retrospective studies. Glycopyrrolate, however, demonstrated significant reduction of hypersalivation in a randomized controlled trial. Medications with activity at α-adrenergic receptors have shown positive results in case reports, retrospective evaluations, and an open-label trial, but have not been investigated in a double-blind, controlled fashion. Botulinum toxin also significantly improved sialorrhea in both a case report and double-blind study, although the trial included hypersalivation from other etiologies in addition to clozapine. Substitute benzamide derivatives have demonstrated significant improvements in randomized controlled trials; however, they are not available in the US. Overall, few treatment strategies have been evaluated in controlled settings, warranting further randomized controlled trials to identify more effective treatment options. CONCLUSIONS: Current pharmacologic treatment options for clozapine-induced sialorrhea are limited in number and efficacy. Although few randomized controlled trials have been conducted, this review identifies potential treatment alternatives for this common and sometimes severe adverse effect.