High-dose zolpidem dependence and detoxification from withdrawal symptoms using diazepam

Objective: Efforts to promote the cessation of harmful alcohol use are hindered by the affective and physiological components of alcohol withdrawal (AW), which can include life-threatening seizures. Although previous studies of AW and relapse have highlighted the critical importance of the N-methyl-D-aspartate receptor (NMDAR) subunit GluN2B and the detrimental role of stress, little is known about genetic risk factors. We therefore conducted genetic and neurobiological studies to identify and characterize novel risk loci. Methods: We performed a genome-wide association study (GWAS) of AW symptom count in uniformly assessed subjects with histories of serious AW, followed by additional genotyping in independent subjects, and bioinformatic analyses. We used genetically modified mouse neuronal cultures to conduct electrophysiological and pharmacological studies of neurobiological systems implicated by the GWAS. Results: The top association signal for AW severity was in sortilin-related gene SORCS2 on chromosome 4 (European-American meta-analysis n = 1,478, P = 4.3 x 10–9), and the same risk allele also predicted more severe clinical outcomes in seizure disorder patients participating in a randomized trial of anticonvulsant effectiveness (n = 654, P = 3.2 x 10–3). In humans, SORCS2 is most highly expressed in the nervous system, and bioinformatic analyses showed that the SORCS2 risk haplotype disrupts transcription factor (TF) binding motifs within a stress hormoneregulated enhancer element active in human hippocampus. In mouse hippocampal preparations, we demonstrate that SorCS2 is a key regulator of GluN2B-mediated synaptic responses. Conclusion: These translational findings identify new synaptic regulatory processes, and provide novel targets for managing the aversive consequences of abrupt alcohol cessation. PM297 High-dose zolpidem dependence and detoxification from withdrawal symptoms using diazepam St. Andrew’s Hospital, Republic of Korea Abstract Objective of the study: Zolpidem is a nonbenzodiazepine hypnotic for the treatment of insomnia, and known as a relatively safe medication. However, there have been several case reports of zolpidem abuse and dependence these days. Even though some withdrawal symptoms like seizures can occur, there was no standard detoxification method until now. Methods used: We reviewed the previous researches about high-dose zolpidem addiction and proposed treatment, and the clinical case. Summary of results: A high dose of zolpidem has similar pharmacologic properties as the rest of benzodiazepines, even though the usual dose of zolpidem has a selectivity to type 1 benzodiazepine receptor. So, some cases of high-dose Zolpidem dependence can be treated by conventional benzodiazepines, such as diazepam. Actually, diazepam tends to be avoided because of complicated pharmacological properties and potential risks like respiratory suppression, iatrogenic dependence. But diazepam is still one of candidate medication for managing withdrawal symptoms of benzodiazepine dependence, and also, nonbenzodiazepine hypnotics in the clinical setting. Conclusions reaches: We report a rare case of high-dose addiction and successful detoxification by cross-titration with diazepam.