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Patients with major depression were treated with an oral γ-aminobutyric acid type A–receptor modulator for 14 days. At day 15, patients who received the drug had a greater reduction in depressive symptoms than patients who received placebo. Headache was the most common adverse event.

Postpartum depression is one of the most common complications of childbirth. Untreated postpartum depression can have substantial adverse effects on the well-being of the mother and child, negatively impacting child cognitive, behavioral, and emotional development with lasting consequences. There are a number of therapeutic interventions for postpartum depression including pharmacotherapy, psychotherapy, neuromodulation, and hormonal therapy among others, most of which have been adapted from the treatment of major depressive disorder outside of the peripartum period. Current evidence of antidepressant treatment for postpartum depression is limited by the small number of randomized clinical trials, underpowered samples, and the lack of long-term follow-up. The peripartum period is characterized by rapid and significant physiological change in plasma levels of endocrine hormones, peptides, and neuroactive steroids. Evidence supporting the role of neuroactive steroids and γ-aminobutyric acid (GABA) in the pathophysiology of postpartum depression led to the investigation of synthetic neuroactive steroids and their analogs as potential treatment for postpartum depression. Brexanolone, a soluble proprietary intravenous preparation of synthetic allopregnanolone, has been developed. A recent series of open-label and placebo-controlled randomized clinical trials of brexanolone in postpartum depression demonstrated a rapid reduction in depressive symptoms, and has led to the submission for regulatory approval to the US Food and Drug Administration (decision due in March 2019). SAGE-217, an allopregnanolone analog, with oral bioavailability, was recently tested in a randomized, double-blind, placebo-controlled phase III study in severe postpartum depression, with reportedly positive results. Finally, a 3β-methylated synthetic analog of allopregnanolone, ganaxolone, is being tested in both intravenous and oral forms, in randomized, double-blind, placebo-controlled phase II studies in severe postpartum depression.

Neuroactive steroids are a large group of substances having effect in the brain and on brain function. The steroids most studied are allopregnanolone (ALLO), tetrahydrodesoxycorticosterone (THDOC), pregnenolone sulfate (PS) dihydroepiandrosteronesulfate (DHEAS), and estradiol (E2). ALLO and THDOC are called gamma-aminobutyric acid (GABA) steroids as they are positive modulators of the GABAA receptor in a similar way as benzodiazepines, barbiturates, and alcohol. GABA steroids not only have similar behavioral effects as benzodiazepines and barbiturates but, possibly, also similar adverse effects as well. This review aims to elucidate the possible role that neuroactive steroids play in the development of mood disorders in women. One of the most clear-cut examples of the interaction between mood, neuroactive steroids, and the GABA system is premenstrual dysphoric disorder (PMDD), which is a cluster of negative mood symptoms occurring during the luteal phase of the menstrual cycle in 2-6% of reproductive women. Furthermore, certain women also experience adverse mood effects during sequential progestin addition to postmenopausal estrogen treatment, which is why the role of neuroactive steroids in postmenopausal women is also addressed in this review.

Background An efficient, well tolerated, and safe emergency treatment with a rapid onset of action is needed to prevent seizure clusters and to terminate prolonged seizures and status epilepticus. Objectives This study aimed to examine the efficacy, tolerability, and safety of intranasal midazolam (in-MDZ) spray in clinical practice. Methods In this retrospective, multicenter observational study, we evaluated all patients with peri-ictal application of in-MDZ during video-EEG monitoring at the epilepsy centers in Frankfurt and Marburg between 2 014 and 2017. For every patient, we analyzed the recurrence of any seizure or generalized tonic–clonic seizures after index seizures with and without in-MDZ administration. Treatment-emergent adverse events (TEAEs) were also evaluated. Results In-MDZ was used in 243 patients with epilepsy (mean age 35.5 years; range 5–76 years; 46.5% female) for treatment of 459 seizures. A median dose of in-MDZ 5 mg (i.e., two puffs; range 2.5–15 mg) was administered within a median time from EEG seizure onset until in-MDZ application of 1.18 min [interquartile range (IQR) 1.27], while median time from clinical seizure onset until in-MDZ administration was 1.08 min (IQR 1.19). In-MDZ was given within 1 min after EEG seizure onset in 171 seizures. An intraindividual comparison of seizures with and without application of in-MDZ was feasible in 171 patients, demonstrating that in-MDZ reduced the occurrence of any (Cox proportional-hazard model p  < 0.001) and generalized tonic–clonic seizure (Cox proportional-hazard model p  = 0.0167) over a period of 24 h. The seizure-free timespan was doubled from a median of 5.0 h in controls to a median of 10.67 h after in-MDZ administration. We additionally clustered in-MDZ administrations for the 119 patients who received in-MDZ more than once, comparing them with the index cases without in-MDZ. Even when considering subsequent seizures with in-MDZ administration, a patient receiving in-MDZ is still half as likely to incur another seizure in the upcoming 24 h as compared with when the same patient does not receive in-MDZ (hazard ratio 0.50; 95% CI 0.42–0.60; p  < 0.01). In-MDZ was well tolerated without major adverse events. The most common side effects were irritation of the nasal mucosa [37 cases (8.1%)], prolonged sedation [26 cases (5.7%)], and nausea and vomiting [12 cases (2.6%)]. A decline in oxygen saturation was measured after 78 seizures (17%). Conclusion We conclude that in-MDZ is a safe and efficient treatment option to prevent short-term recurrence of seizures. In-MDZ can be administered very quickly by trained staff within 1–2 min after seizure onset. No major cardiocirculatory or respiratory adverse events were observed.

Key Points The incidence of insomnia in the general population is 10–30% and approximately 50% of cases complain of serious daytime consequences, such as inability to concentrate, reduced energy and memory problems. However, the development of hypnotic drugs tends to focus on the marginal and statistically significant increase in minutes slept during the night instead of the effects on the quality of wakefulness. Current hypnotics, such as benzodiazepine receptor agonists, antihistamines and antidepressants, can be effective short-term treatments, but they can also cause next-day sedation, ataxia and cognitive impairment. Advances in the understanding of sleep mechanisms have indicated new approaches for discovering novel hypnotic drugs. For example, the enhancement of slow-wave sleep and the modulation of circadian rhythms are strategies being pursued in the development of improved insomnia therapeutics. The use of primary insomniacs as the key population for clinical development of hypnotics is limiting novel treatments of insomnia. Focus should be on the development of compounds with restorative effects on daytime function rather than on induction and maintenance of sleep only. Development of hypnotics in secondary insomniacs may address the relevant effects of sleep on quality of life and daytime performance. In this Review Ebert and Wafford discuss the mechanisms of action of current and emerging hypnotic drugs, emphasizing the importance of taking into account the consequences of disrupted sleep on day-time performance (or quality of wakefulness) when developing new therapeutics. Sleep is essential for our physical and mental well being. However, when novel hypnotic drugs are developed, the focus tends to be on the marginal and statistically significant increase in minutes slept during the night instead of the effects on the quality of wakefulness. Recent research on the mechanisms underlying sleep and the control of the sleep–wake cycle has the potential to aid the development of novel hypnotic drugs; however, this potential has not yet been realized. Here, we review the current understanding of how hypnotic drugs act, and discuss how new, more effective drugs and treatment strategies for insomnia might be achieved by taking into consideration the daytime consequences of disrupted sleep.

Background and Objective Pregabalin abuse and dependence has been increasingly described; however, it is not described in France. Our study aimed to investigate the abuse and dependence potential of pregabalin by a disproportionality analysis, in the French Pharmacovigilance Database (FPVD), in comparison with amitriptyline and clonazepam. Methods We performed a case/noncase study in the FPVD. Between January, 1 2010 and December, 31 2015, we identified cases of abuse and or dependence (excluding isolated withdrawal syndromes) using MedDRA (Medical Dictionary for Regular Activities) terms. Exposure to pregabalin was defined as the mention of pregabalin in the report. Clonazepam was used as positive control and amitriptyline as negative control. Results Among the 184,310 reports in the database, 521 were abuse or dependence cases. Exposure to pregabalin was found in eight (1.5 %) of them. We did not find any significant association between exposure to pregabalin and drug abuse or dependence: reporting odds ratio (ROR) = 1.1 95 % confidence interval (CI) (0.6–2.3). ROR for clonazepam was 5.7 95 % CI (3.5–9.2). No case of an amitriptyline-related abuse or dependence was recorded in the FPVD. Conclusions The first cases of pregabalin-related abuse or dependence reported in France occurred later than in other European countries, since none had been described before 2010. This analysis in the FPVD did not find a higher proportion of abuse/dependence with pregabalin in comparison with other drugs. Considering evidence of pregabalin abuse worldwide, this analysis underlines the limitations of spontaneous reporting system in the field of addictovigilance.

Recent experimental evidence identified GABAergic sedation as a possible cause for deprived neuroregeneration and poor outcome after acute brain injury. Patients with aneurysmal subarachnoid hemorrhage are often sedated, and GABAergic sedation, such as midazolam and propofol, is commonly used. Retrospective cohort study based on a prospectively established database. Single-center neurointensive care unit. Twenty-nine patients after subarachnoid hemorrhage. Noninterventional study. The relationship between mean GABAergic sedative dose during the acute phase and outcome after 6 months according to the Glasgow Outcome Scale, and initial Glasgow Coma Scale was investigated. Use of GABAergic sedatives was negatively correlated with Glasgow Outcome Scale (r2=0.267; P=.008). Administration of sedatives was independent of the initial Glasgow Coma Scale. GABAergic sedatives flunitrazepam, midazolam, and propofol were used differently during the first 10 days after ictus. Administration of GABAergic sedation was associated with an unfavorable outcome after 6 months. To avoid bias (mainly through the indication to use sedation), additional experimental and comparative clinical investigation of, for example, non-GABAergic sedation, and clinical protocols of no sedation is necessary. •Continue our work with focus on use of sedatives after acute brain injury.•Hot Topic (Coburn, Pandharipande, Sanders. Crit Care Med 2014 Jan;42(1):211-212).•Supporting sedation free sedation protocols and non-GABAergic drugs for sedation.•Linear correlation between worse outcome and administration GABAergic drugs.

Both alcohol withdrawal syndrome (AWS) and benzodiazepines can cause delirium. Benzodiazepine-associated delirium can complicate AWS and prolong hospitalization. Benzodiazepine delirium can be diagnosed with flumazenil, a GABA-A receptor antagonist. By reversing the effects of benzodiazepines, flumazenil is theorized to exacerbate symptoms of AWS and precludes its use. For patients being treated for alcohol withdrawal, flumazenil can diagnose and treat benzodiazepine delirium without precipitating serious or life-threatening adverse events. Hospital admission records were retrospectively reviewed for patients with the diagnosis of AWS who received both benzodiazepines and flumazenil from December 2006 to June 2012 at a university-affiliated inpatient toxicology center. The day of last alcohol consumption was estimated from available blood alcohol content or subjective history. Corresponding benzodiazepine, flumazenil, and adjunctive sedative pharmacy records were reviewed, as were demographic, clinical course, and outcome data. Eighty-five patients were identified (average age 50.3 years). Alcohol concentrations were detectable for 42 patients with average 261 mg/dL (10–530 mg/dL). Eighty patients were treated with adjunctive agents for alcohol withdrawal including antipsychotics ( n  = 57), opioids ( n  = 27), clonidine ( n  = 35), and phenobarbital ( n  = 23). Average time of flumazenil administration was 4.7 days (1–11 days) after abstinence, and average dose was 0.5 mg (0.2–1 mg). At the time of flumazenil administration, delirium was described as hypoactive ( n  = 21), hyperactive ( n  = 15), mixed ( n  = 41), or not specified ( n  = 8). Response was not documented in 11 cases. Sixty-two (72.9 %) patients had significant objective improvement after receiving flumazenil. Fifty-six patients required more than one dose (average 5.6 doses). There were no major adverse events and minor adverse effects included transiently increased anxiety in two patients: 1 patient who received 0.5 mg on abstinence day 2 and another patient who received 0.2 mg flumazenil on abstinence day 11. This is the largest series diagnosing benzodiazepine delirium after AWS in patients receiving flumazenil. During the treatment of AWS, if delirium is present on day 5, a test dose of flumazenil may be considered to establish benzodiazepine delirium. With the limited data set often accompanying patients with AWS, flumazenil diagnosed benzodiazepine delirium during the treatment of AWS and improved impairments in cognition and behavior without serious or life-threatening adverse events in our patients.

Background Practice guidelines recommend the use of low dose haloperidol when medication is needed to treat delirium with acute agitation in hospitalized older people. Despite this, high dose haloperidol may frequently be used and result in higher rates of complications. Objective To describe dosages and effects of haloperidol used in the initial treatment of delirium with acute agitation in hospitalized older people, and prescriber use of low and high dose haloperidol. Methods Retrospective chart reviews were performed from June 2008 to May 2009 in a community teaching hospital located in Upland, PA, USA. Patients aged 65 years and older with acute agitated delirium were included. Patients admitted to ICU and those with psychiatric conditions were excluded. Data were collected on haloperidol dosing, responses, sedation, length of stay, and concurrent use of lorazepam. Results A total of 261 charts of patients who received haloperidol were reviewed and 56 patients met inclusion criteria (14 males, 42 females). The mean age of subjects was 83 years. The recommended starting dose of haloperidol (0.5 mg) was administered to 35.7 % of the patients. An initial dose of more than 1 mg was received by 37.5 % of the patients. The remaining 26.8 % of patients received 1 mg. The relative risk of sedation was significantly greater for subjects receiving more than 1 mg of haloperidol in 24 h. The length of hospitalization was not predicted by haloperidol doses or lorazepam but by the number of days of agitation. Conclusions Higher than recommended initial doses of haloperidol were frequently used in the treatment of delirium with acute agitation in hospitalized older people. We found no evidence to suggest that higher dosages were more effective in decreasing the duration of agitation or the length of hospital stay. Low dose haloperidol appears to be as effective as and safer than higher doses in the treatment of acute agitation in this older population.

Benzodiazepine drugs are controversial because of safety and abuse liability concerns, although they have clinically relevant pharmacological differences. The current article reviews studies pertaining to the pharmacology, safety, and abuse liability of oxazepam. Compared to other benzodiazepine drugs, oxazepam has a favorable safety and abuse liability profile, which may be related to its pharmacology. Oxazepam is more slowly absorbed and enters the brain more slowly than other benzodiazepine drugs; it does not have active metabolites and does not accumulate with chronic dosing; its metabolism is not affected by age or by mild/moderate liver disease; and it is not prone to drug–drug interactions. Oxazepam also binds to the translocator protein, which stimulates the synthesis of neurosteroids, and this effect may contribute to its reduced abuse liability. [ Journal of Psychosocial Nursing and Mental Health Services, 54 (4), 22–25.]