Open-label, proof-of-concept study of brexanolone in the treatment of severe postpartum depression

Preclinical evidence indicates that rapid changes in levels of allopregnanolone, the predominant metabolite of progesterone, confer dramatic behavioral changes and may trigger postpartum depression (PPD) in some women. Considering the pathophysiology of PPD (i.e., triggered by reproductive steroids), the need for fast‐acting, efficacious treatments and the negative consequences of untreated PPD, there is an increasing focus on developing PPD therapies. Brexanolone (USAN; formerly SAGE‐547 Injection), a proprietary injectable allopregnanolone formulation, was evaluated as a treatment for severe PPD in a proof‐of‐concept, open‐label study

Trial of SAGE-217 in Patients with Major Depressive Disorder

BACKGROUND: Altered neurotransmission of gamma-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 \u3c 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.)

Pharmacokinetic and behavioral characterization of a longterm antipsychotic delivery system in rodents and rabbits

Rationale: Non-adherence with medication remains the major correctable cause of poor outcome in schizophrenia. However, few treatments have addressed this major determinant of outcome with novel long-term delivery systems. Objectives: The aim of this study was to provide biological proof of concept for a long-term implantable antipsychotic delivery system in rodents and rabbits. Materials and methods: Implantable formulations of haloperidol were created using biodegradable polymers. Implants were characterized for in vitro release and in vivo behavior using prepulse inhibition of startle in rats and mice, as well as pharmacokinetics in rabbits. Results: Behavioral measures demonstrate the effectiveness of haloperidol implants delivering 1 mg/kg in mice and 0.6 mg/kg in rats to block amphetamine (10 mg/kg) in mice or apomorphine (0.5 mg/kg) in rats. Additionally, we demonstrate the pattern of release from single polymer implants for 1 year in rabbits. Conclusions: The current study suggests that implantable formulations are a viable approach to providing long-term delivery of antipsychotic medications in vivo using animal models of behavior and pharmacokinetics. In contrast to depot formulations, implantable formulations could last 6 months or longer. Additionally, implants can be removed throughout the delivery interval, offering a degree of reversibility not available with depot formulations

Constitutive activation of the G-protein subunit G&#945;s within forebrain neurons causes PKA-dependent alterations in fear conditioning and cortical <i>Arc</i> mRNA expression

Memory formation requires cAMP signaling; thus, this cascade has been of great interest in the search for cognitive enhancers. Given that medications are administered long-term, we determined the effects of chronically increasing cAMP synthesis in the brain by expressing a constitutively active isoform of the G-protein subunit G&#945;s (G&#945;s*) in postnatal forebrain neurons of mice. Previously, we showed that G{alpha}s* mice exhibit increased adenylyl cyclase activity but decreased cAMP levels in cortex and hippocampus due to a PKA-dependent increase in total cAMP phosphodiesterase (PDE) activity. Here, we extend previous findings by determining if G&#945;s* mice show increased activity of specific PDE families that are regulated by PKA, if G&#945;s* mice show PKA-dependent deficits in fear memory, and if these memory deficits are associated with PKA-dependent alterations in neuronal activity as mapped by Arc mRNA expression. Consistent with previous findings, we show here that G&#945;s* mice exhibit a significant compensatory increase in cAMP PDE1 activity and a trend toward increased cAMP PDE4 activity. Further, inhibiting the presumably elevated PKA activity in G&#945;s* mice fully rescues short- and long-term memory deficits in a fear-conditioning task, while extending the training session from one to four CSUS pairings partially rescues these deficits. Mapping of Arc mRNA levels suggests these PKA-dependent memory deficits may be related to decreased neuronal activity specifically within the cortex. G&#945;s* mice show decreased Arc mRNA expression in CA1, orbital cortex, and cortical regions surrounding the hippocampus; however, only the deficits in cortical regions surrounding the hippocampus are PKA dependent. Our results imply that chronically stimulating targets upstream of cAMP may detrimentally affect cognition

Effect of Zuranolone on Concurrent Anxiety and Insomnia Symptoms in Women With Postpartum Depression

Concurrent anxiety and/or insomnia symptoms in women with postpartum depression (PPD) are common and associated with more severe PPD. The effects of zuranolone on concurrent anxiety and/or insomnia symptoms and on patient-perceived functional health in women with PPD in the ROBIN study are reported. The phase 3, double-blind, randomized, placebo-controlled trial (conducted January 2017-December 2018) included women aged 18-45 years, ≤ 6 months postpartum, with PPD (onset of -defined major depressive episode in the third trimester or ≤ 4 weeks postpartum) and baseline 17-item Hamilton Depression Rating Scale (HDRS-17) total score ≥ 26. Women were randomized 1:1 to once-daily oral zuranolone 30 mg (n = 77) or placebo (n = 76) for 14 days with follow-up through day 45. Concurrent remission of depressive and anxiety symptoms (Hamilton Anxiety Rating Scale total score ≤ 7 plus HDRS-17 total score ≤ 7 or Montgomery-Asberg Depression Rating Scale total score ≤ 10), improvement in insomnia symptoms, patient-perceived functional health, and treatment effect sizes described by number needed to treat (NNT) were assessed. Analyses were exploratory; values are nominal. Rates of concurrent remission of depressive and anxiety symptoms were higher with zuranolone versus placebo  \u3c .05) at days 3, 15, and 45; the rate of sustained concurrent remission (ie, at both days 15 and 45) was also higher with zuranolone ( \u3c .05). Anxiety symptoms (assessed by HDRS-17 anxiety/somatization subscale and Edinburgh Postnatal Depression Scale anxiety subscale) improved with zuranolone versus placebo ( \u3c .05) at days 3 through 45. Potential benefits on insomnia symptoms and patient-perceived functional health were observed. Day 15 NNTs were 5 for both HDRS-17 response and remission. Zuranolone was associated with concurrent improvements in depressive and anxiety symptoms, with beneficial effects on insomnia symptoms and patient-perceived functional health in adults with PPD. ClinicalTrials.gov identifier: NCT02978326

Constitutive activation of G alpha s within forebrain neurons causes deficits in sensorimotor gating because of PKA-dependent decreases in cAMP

Sensorimotor gating, the ability to automatically filter sensory information, is deficient in a number of psychiatric disorders, yet little is known of the biochemical mechanisms underlying this critical neural process. Previously, we reported that mice expressing a constitutively active isoform of the G-protein subunit Galphas (Galphas*) within forebrain neurons exhibit decreased gating, as measured by prepulse inhibition of acoustic startle (PPI). Here, to elucidate the biochemistry regulating sensorimotor gating and to identify novel therapeutic targets, we test the hypothesis that Galphas* causes PPI deficits via brain region-specific changes in cyclic AMP (cAMP) signaling. As predicted from its ability to stimulate adenylyl cyclase, we find here that Galphas* increases cAMP levels in the striatum. Suprisingly, however, Galphas* mice exhibit reduced cAMP levels in the cortex and hippocampus because of increased cAMP phosphodiesterase (cPDE) activity. It is this decrease in cAMP that appears to mediate the effect of Galphas* on PPI because Rp-cAMPS decreases PPI in C57BL/6J mice. Furthermore, the antipsychotic haloperidol increases both PPI and cAMP levels specifically in Galphas* mice and the cPDE inhibitor rolipram also rescues PPI deficits of Galphas* mice. Finally, to block potentially the pathway that leads to cPDE upregulation in Galphas* mice, we coexpressed the R(AB) transgene (a dominant-negative regulatory subunit of protein kinase A (PKA)), which fully rescues the reductions in PPI and cAMP caused by Galphas*. We conclude that expression of Galphas* within forebrain neurons causes PPI deficits because of a PKA-dependent decrease in cAMP and suggest that cAMP PDE inhibitors may exhibit antipsychotic-like therapeutic effects

Burden of illness for super-refractory status epilepticus patients

<p><b>Objective:</b> To provide an estimate of the annual number of super-refractory status epilepticus (SRSE) cases in the United States (US) and to evaluate utilization of hospital resources by these patients.</p> <p><b>Methods:</b> The Premier Hospital Database was utilized to estimate the number of SRSE cases based on hospital discharges during 2012. Discharges were classified as SRSE cases based on an algorithm using seizure-related International Classification of Diseases-9 (ICD-9) codes, Intensive Care Unit (ICU) length of stay (LOS), and treatment protocols (e.g., benzodiazepines, antiepileptic drugs (AEDs), and ventilator use). Secondary analyses were conducted using more restrictive algorithms for SRSE.</p> <p><b>Results:</b> A total of 6,325 hospital discharges were classified as SRSE cases from a total of 5,300,000 hospital discharges. Applying a weighting based on hospital characteristics and 2012 US demographics, this projected to an estimated 41,156 cases of SRSE in the US during 2012, an estimated incidence rate of approximately 13/100,000 annually for SRSE in the US. Secondary analyses using stricter SRSE algorithms resulted in estimated incidence rates of approximately 11/100,000 and 8/100,000 annually. The mean LOS for SRSE hospitalizations was 16.5 days (median = 11; interquartile range [IQR] = 6–20), and the mean LOS in ICU was 9.3 days (median = 6; IQR = 3–12). The mean cost of an SRSE hospitalization was $51,247 (median=$33,294; 95% CI=$49,634–$52,861).</p> <p><b>Limitations:</b> The analysis uses ICD-9 diagnostic codes and claims information, and there are inherent limitations in any methodology based on treatment protocol, which created challenges in distinguishing with complete accuracy between SRSE, RSE, and SE on the basis of care patterns in the database.</p> <p><b>Conclusion:</b> SRSE is associated with high mortality and morbidity, which place a high burden on healthcare resources. Projections based upon the findings of this study suggest an estimated 25,821 to 41,959 cases of SRSE may occur in the US each year, but more in-depth studies are required.</p