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Buprenorphine/samidorphan (BUP/SAM), a combination of BUP (a µ-opioid receptor partial agonist and κ-antagonist) and SAM (a sublingually bioavailable µ-opioid antagonist), is an investigational opioid system modulator for depression. BUP/SAM has shown efficacy versus placebo as an adjunctive treatment for major depressive disorder (MDD) and a consistent safety profile in previously reported, placebo-controlled clinical studies.1,2
1. To characterize the safety profile following long-term treatment with BUP/SAM
2. To explore depression symptoms and remission rates in patients with MDD following long-term treatment with BUP/SAM
FORWARD-2 (Clinicaltrials.gov ID: NCT02141399) enrolled patients who had participated in 1 of 4 controlled studies as well as de novo patients. All patients had a confirmed diagnosis of MDD, had a history of inadequate response to standard antidepressant therapies (ADTs), and had been treated with an adequate dose of an established ADT for ≥8weeks before BUP/SAM initiation. ADT dosage could be titrated, but the ADT could not be changed. During the study, patients received open-label, sublingual BUP/SAM 2mg/2mg as adjunctive treatment for up to 52weeks. Safety (primary objective) was assessed via adverse events (AEs), vital signs, laboratory analytes, and electrocardiography. Suicidal ideation or behavior (SIB) was evaluated by the Columbia Suicide Severity Rating Scale. Abuse potential, dependence, and withdrawal were assessed by AEs and the Clinical Opiate Withdrawal Scale. Exploratory efficacy endpoints included mean Montgomery–Åsberg Depression Rating Scale (MADRS) scores and remission rate (MADRS ≤10).
Of 1454 total patients, 49% completed the 52-week study, 11% discontinued due to an AE, and 40% discontinued because of other reasons as of the interim data cutoff date (April 30, 2017). Most AEs were of mild/moderate severity. Serious AEs were reported in 3.2% of patients. AEs occurring in ≥10% of patients were nausea, headache, constipation, dizziness, and somnolence. There was no evidence of increased risk of SIB with BUP/SAM. Incidence of euphoria-related events was low (1.2%). After abrupt discontinuation of BUP/SAM, there was little evidence of withdrawal. BUP/SAM was not associated with meaningful changes in laboratory or metabolic parameters or in bodyweight. The mean MADRS score decreased from 22.9 (±9.7) at baseline to 9.8 (±8.8) after 52weeks. The remission rate at 52weeks was 52.5%.
Long-term treatment with BUP/SAM did not reveal any new safety findings and confirmed that the risk of abuse and dependence with BUP/SAM was low. BUP/SAM maintained an antidepressant effect for up to 52weeks of treatment in patients with MDD.
Buprenorphine (BUP)/samidorphan (SAM) combination is an opioid system modulator being investigated as an adjunctive treatment for major depressive disorder (MDD). BUP/SAM is a fixed-dose combination of BUP, a partial µ-opioid receptor agonist and κ-opioid receptor antagonist, and SAM, a µ-opioid receptor antagonist added to address the abuse and dependence potential of BUP.1,2
We assessed the effects of SAM on the abuse potential of BUP in the BUP/SAM combination in two ways: (1) a human abuse potential (HAP) study in volunteers; and (2) an evaluation of the clinical experience across studies of patients with MDD.
Study 212 (ClinicalTrials.gov ID: NCT02413281) was a HAP study in nondependent, recreational, adult opioid users. Following a qualification period, participants were randomized to 6 treatments in a blinded, crossover design: placebo (PBO), BUP/SAM at the target therapeutic dose (BUP/SAM 2mg/2mg), at 8mg/8mg and 16mg/16mg , and BUP alone (8mg and 16mg). The primary endpoint was maximum effect (Emax) for “At The Moment” Drug Liking Visual Analog Scale (VAS).
The clinical program for BUP/SAM included 4 PBO-controlled studies of patients with MDD (n=961). Pooled safety data were evaluated for adverse events (AEs) that may be associated with abuse, dependence, or withdrawal, as well as for objective signs of withdrawal with the Clinical Opioid Withdrawal Scale (COWS).
In Study 212 (n=38), Emax Drug Liking VAS scores for the BUP/SAM 2mg/2mg dose were similar to those for PBO (median within-subject difference [90% CI]: 2.5 [0.0–9.0]). Emax Drug Liking VAS scores for all BUP/SAM dose groups, including supratherapeutic doses, were significantly lower than those observed for either of the BUP doses. The supratherapeutic doses of BUP/SAM (8mg/8mg and 16mg/16mg) had higher Emax Drug Liking VAS scores than PBO, but the differences were small.
In the MDD controlled studies, the incidence of euphoria-related AEs was low for BUP/SAM 2mg/2mg and PBO (1.6% vs 0.2%, respectively) and there was no evidence of abuse or dependence behavior. Euphoria-related events typically occurred with treatment initiation and resolved with continued treatment. There was minimal evidence of withdrawal by reported AEs or COWS assessment.
These findings indicate that SAM mitigates the abuse potential of BUP in the BUP/SAM combination.
A new optical delivery system has been developed for the (scanning) transmission electron microscope. Here we describe the in situ and “rapid ex situ” photothermal heating modality of the system, which delivers >200 mW of optical power from a fiber-coupled laser diode to a 3.7 μm radius spot on the sample. Selected thermal pathways can be accessed via judicious choices of the laser power, pulse width, number of pulses, and radial position. The long optical working distance mitigates any charging artifacts and tremendous thermal stability is observed in both pulsed and continuous wave conditions, notably, no drift correction is applied in any experiment. To demonstrate the optical delivery system’s capability, we explore the recrystallization, grain growth, phase separation, and solid state dewetting of a Ag0.5Ni0.5 film. Finally, we demonstrate that the structural and chemical aspects of the resulting dewetted films was assessed.
Safety and tolerability of long-term treatment with the long-acting antipsychotic aripiprazole lauroxil (AL) were evaluated in patients with schizophrenia.
This was an international, multicenter, phase 3, 52-week safety study of 2 fixed doses of AL (441 mg or 882 mg intramuscular every 4 weeks). Safety endpoints included adverse events (AEs) and extrapyramidal symptoms (EPS) including akathisia, injection-site reactions (ISRs), and clinically relevant changes in metabolic and endocrine values.
Of 478 patients entering this study, 236 (49%) continued from a previous 12-week, phase 3 efficacy study of AL, and 242 (51%) were newly enrolled. Overall, 77% and 23% of patients received AL 882 mg (N = 368) and 441 mg (N = 110), respectively. AEs occurred in 50.4% of patients; most were mild (28.7%) or moderate (18.2%). The most common AEs were insomnia (8.4%) and increased weight (5.0%). Akathisia was reported as an AE in 3.8% of the overall population, with higher rates in patients initiating AL on study entry than those continuing on AL. EPS-related AEs occurred in 9.4% of patients, and AEs related to metabolic parameters were reported in 4.6% of patients. Weight gain was minimal (0.8 kg), and no clinically relevant changes were observed for metabolic parameters. The overall incidence of ISRs was 3.8%; most were associated with the initial injections in patients receiving their first injection in this study.
Long-term treatment with AL is generally well tolerated, with a safety profile consistent with that of oral aripiprazole. It is a suitable option for patients with schizophrenia.
Switching antipsychotic medications is common in patients with schizophrenia who are experiencing persistent symptoms or tolerability issues associated with their current drug regimen. This analysis assessed the safety of switching from an oral antipsychotic to the long-acting injectable antipsychotic aripiprazole lauroxil (AL).
This was a post hoc analysis of outpatients with schizophrenia who were prescribed an oral antipsychotic and who enrolled in an international, open-label, long-term (52-week) safety study of AL. The analysis focused on the first 3 injections of AL 882 mg over 12 weeks, divided into the immediate 4-week crossover period between the first and second AL injections (initiation phase) and the subsequent 8 weeks (stabilization phase). Patients were grouped by preswitch oral antipsychotic medication, and safety and clinical symptoms were assessed.
In total, 190 patients had switched from one of the following oral antipsychotic medications: aripiprazole, conventional antipsychotics, risperidone/paliperidone, olanzapine, or quetiapine. The 12-week completion rate was high (92.1%) and similar across the different preswitch oral antipsychotic groups. Overall, adverse event (AE) rates experienced over 12 weeks were modest; no AEs were considered serious. The most common AEs in the initiation phase were injection site pain (5.8%), insomnia (5.8%), and akathisia (3.2%). No apparent relationship was observed between preswitch medication and early-onset AEs. Mean Positive and Negative Syndrome Scale total scores remained stable during this period across preswitch antipsychotic groups.
Switching from an oral antipsychotic to AL was feasible in an outpatient setting for patients with schizophrenia, and the 12-week retention rate was favorable.
Surface adsorption represents a competition between collision and scattering processes that depend on surface energy, surface structure and temperature. The surface reactivity of the actinides can add additional complexity due to radiological dissociation of the gas and electronic structure. Here we elucidate the chemical bonding of gas molecules adsorbed on Pu metal and oxide surfaces. Atmospheric gas reactions were studied at 190 and 300 K using x-ray photoelectron spectroscopy. Evolution of the Pu 4f and O 1s core-level states were studied as a function of gas dose rates to generate a set of Langmuir isotherms. Results show that the initial gas dose forms Pu2O3 on the Pu metal surface followed by the formation of PuO2 resulting in a layered oxide structure. This work represents the first steps in determining the activation energy for adsorption of various atmospheric gases on Pu.
Social dysfunction is a hallmark symptom of schizophrenia which commonly precedes the onset of psychosis. It is unclear if social symptoms in clinical high-risk patients reflect depressive symptoms or are a manifestation of negative symptoms.
We compared social function scores on the Social Adjustment Scale-Self Report between 56 young people (aged 13–27 years) at clinical high risk for psychosis and 22 healthy controls. The cases were also assessed for depressive and ‘prodromal’ symptoms (subthreshold positive, negative, disorganized and general symptoms).
Poor social function was related to both depressive and negative symptoms, as well as to disorganized and general symptoms. The symptoms were highly intercorrelated but linear regression analysis demonstrated that poor social function was primarily explained by negative symptoms within this cohort, particularly in ethnic minority patients.
Although this study demonstrated a relationship between social dysfunction and depressive symptoms in clinical high-risk cases, this association was primarily explained by the relationship of each of these to negative symptoms. In individuals at heightened risk for psychosis, affective changes may be related to a progressive decrease in social interaction and loss of reinforcement of social behaviors. These findings have relevance for potential treatment strategies for social dysfunction in schizophrenia and its risk states and predict that antidepressant drugs, cognitive behavioral therapy and/or social skills training may be effective.
Optimal conditions were determined for performing antibody measurements (ELISA), lymphocyte transformation tests and, to some extent, skin tests in badgers. These parameters, together with the bacteriological and pathological studies reported previously (Pritchard et al. 1987), were used to follow the course of intradermal and intratracheal challenge of badgers with bovine tubercle bacilli. Two challenge doses were used for each route of infection and two animals received each dose. None of the four animals challenged by the intratracheal method showed any evidence of infection, suggesting that adult badgers may have some resistance to challenge by this method. All four animals challenged intradermally developed lesion of tuberculosis.
Immunologically the disease passed through three phases. There was an early phase in which lymphocyte transformation to whole BCG steadily and significantly increased, and skin tests to tuberculin became positive but there was little change in antibody levels. This was followed by an intermediate phase of variable skin responses, fluctuating lymphocyte transformation and significant increase in antibody levels. The final phase, which was only seen in two animals with extensive disease, was associated with changing skin reactions and falling lymphocyte responses, together with a sudden increase in antibody levels.
This paper presents the first formal evidence of cell-mediated immunity to tuberculosis in the badger, which may delay onset and prolong the survival of challenged animals.
The preparation of a skin test antigen from Mycobacterium ulcerans by ultrasonic disintegration and filtration is described. The reagent, called Burulin, was tested in Africa in normal school children, and in patients with leprosy, tuberculosis or M. ulcerans disease. Those with tuberculosis or M. ulcerans disease were simultaneously tested with Tuberculin PPD. Burulin was found to be highly specific for patients in the reactive stage of M. ulcerans disease, and there was no cross-reaction in patients with other mycobacterioses. On the other hand, the majority of patients with M. ulcerans disease reacting to Burulin also produce positive reactions to Tuberculin PPD.
Evidence of past zoonotic infection was investigated serologically in randomly selected Northern Ireland farmers. The percentage of farmers with antibody was: Brucella abortus (0·7), Leptospira interrogans serovars (8·1), Borrelia burgdorferi (14·3), Toxoplasma gondii (73·5), Coxiella burnetii (28·0), Chlamydia psittaci (11·1) and Hantavirus (1·2).
The results show that Northern Ireland farmers have been exposed in the past to zoonotic infections. It is not known if these infections contributed to ill health in farmers but it is now time for the health of farm workers and their medical services to be reassessed.
Captive, healthy, adult badgers have blood containing haemoglobin at 13·3 g/dl, and 8·4×1012/l red cells with an MCV of 46·2 f1 and an MCH of 15·6 pg. They have 5·1×109 white cells/1 of which 3·29×109 are polymorphs, 1·49×109 are lymphocytes, 0·26×109 are monocytes, 0·07×109 are eosinophils and 0·01×109 are basophils. These values are somewhat less in adult animals just trapped from the wild, and are lower still in wild cubs.
Changes associated with tuberculosis are a rise, and then a fall in red blood count and white blood count, an increase in the proportion of polymorphs and momocytes and a fall in lymphocytes late in the disease. This picture is similar to that seen in widespread, disseminated, tuberculin negative, tuberculosis in humans, a type of disease similar to that occurring in many badgers.
BCG vaccination of badgers did not produce any measurable change in the blood picture.
A range of new Tubercul ns prepared from extracts of living organisms belonging to 12 mycobacterial species has been used to assess the effect of BCG immunization and contact with environmental mycobacteria on Ugandan adults. A total of 2,456 tests were carried out on 562 people, 86% of whom came from three areas selected for special study. These areas were chosen on the basis of occurrence of leprosy and M. ulcerans infection and on data concerning the distribution of environmental mycobacteria. It was found that the effect of BCG was small compared with that previously observed amongst Kenyan schoolchildren, but that the effect of geographical origin was considerable. There was some correlation between the percentages of reactivity to the reagents and the frequency of mycobacteria in the environment.
Impairments in executive cognitive control, including a reduced ability to inhibit prepotent responses, have been reported in autism spectrum disorders (ASD). These deficits may underlie patterns of repetitive behaviors associated with the disorder.
Eighteen individuals with ASD and 15 age- and IQ-matched healthy individuals performed an antisaccade task and a visually guided saccade control task, each with gap and overlap conditions. Measures of repetitive behaviors were obtained using the Autism Diagnostic Inventory – Revised (ADI-R) and examined in relation to neurocognitive task performance.
Individuals with an ASD showed increased rates of prosaccade errors (failures to inhibit prepotent responses) on the antisaccade task regardless of task condition (gap/overlap). Prosaccade error rates were associated with the level of higher-order (e.g. compulsions, preoccupations) but not sensorimotor repetitive behaviors in ASD.
Neurocognitive disturbances in voluntary behavioral control suggest that alterations in frontostriatal systems contribute to higher-order repetitive behaviors in ASD.
Summary of treatment modalities in psychiatric disorders
Antonio Mantovani, Department of Psychiatry Division of Brain Stimulation and Therapeutic Modulation New York State Psychiatric Institute NY USA,
Arielle D. Stanford, Department of Psychiatry Division of Brain Stimulation and Therapeutic Modulation New York State Psychiatric Institute New York, NY USA,
Peter Bulow, Department of Psychiatry Division of Brain Stimulation and Therapeutic Modulation New York State Psychiatric Institute NY USA,
Sarah H. Lisanby, Department of Psychiatry Columbia University; Department of Biological Psychiatry New York State Psychiatric Institute NY USA
Peter Tyrer, Imperial College of Science, Technology and Medicine, London,Kenneth R. Silk, University of Michigan, Ann Arbor
This chapter illustrates how fast-growing are effective treatments in psychiatry. Twenty years ago the contents of this chapter would hardly be understood by the average clinician; now each new treatment is hammering on the door of clinical practice demanding to be let in. The most researched treatment is transcranial magnetic stimulation (TMS); this has been shown clearly to have antidepressant efficacy and, although not as effective as ECT in severe depression, has fewer adverse effects. All the other treatments are really at the early stage of clinical experience and are not first-line treatments. Magnetic seizure therapy and vagus nerve stimulation may have a role in treatment-resistant depression and deep brain stimulation (DBS) is likely to replace the various forms of leucotomy still practiced in some parts of the world, mainly because DBS can be controlled and directed so much more specifically than the older treatments. Transcranial direct current stimulation (tDCS) may also have antidepressant effects but more studies are needed. We will all be hearing more about these new treatments which have the potential to replace ECT, leucotomy and related treatments entirely.
Advances in the science and technology of neuromodulation over the past two decades have led to several interventions that have rekindled clinical and research interest in nonpharmacological somatic therapies. Although electroconvulsive therapy (ECT) remains the only somatic treatment with widespread acceptance and application based upon 70 years of clinical use, transcranial magnetic stimulation (TMS), magnetic seizure therapy (MST), vagus nerve stimulation (VNS), deep brain stimulation (DBS) and transcranial direct current stimulation (tDCS), all offer novel means of potentially treating neuropsychiatric conditions and may provide a better understanding of the brain pathophysiology of these disorders.
Using the 2dF multi-fibre instrument on the Anglo-Australian Telescope, moderate resolution spectra have been obtained for a large sample of stars on the main sequence and at the turnoff in the unusual globular cluster ω Cen. We investigate the behaviour of CH, CN and SrII line strength indices as a function of overall abundance for the main sequence sample. A number of stars do not follow the relations defined by the majority. These anomalous objects can be categorized into (at least) three types. (1) Carbon enhanced stars, which represent about 5% of the sample, and which are found at all metallicities. Spectrum synthesis calculations show that the atmospheres of these stars are typically enhanced in carbon by factors of between 3 and 10. (2) Nitrogen enhanced stars, revealed for [Fe/H] [ges ]–1.3 by strong CN indices, which make up ∼40% of the cluster main sequence population above this metallicity. The stars are enhanced in nitrogen by factors of up to 100. Our data, however, provide no constraints on their relative numbers at lower [Fe/H]. (3) Stars with enhancements of the s-process element Sr by factors of 30 to 60. The possible origins for these abundance anomalies are discussed.
Mental health problems affect a sizeable minority of Australian adolescents. Depression and substance use disorders are common mental disorders reported in this age group. Difficulties of this nature that manifest in adolescence will often continue into adulthood. This report describes a sample of adolescents referred to a public mental health service with respect to their psychiatric diagnoses, depressive symptoms, patterns of substance use and level of suicidality. Mood disorders and substance-use disorders were both prevalent in the sample of participants, with sizeable comorbidity reflected in the number ol participants meeting criteria for both of these diagnoses. Data revealed participants with a psychiatric diagnosis were significantly more likely to have made a suicide attempt than those with no diagnosis. High levels of depressive symptoms were associated with suicidality, illicit substance use, and the likelihood of having a psychiatric diagnosis. Heavy use of alcohol was prevalent in this group, but unrelated to the other variables of interest to the study. These results are discussed with respect to the importance of early detection of vulnerable students in a school setting.
This book owes its origins to a desire to bring together two divergent approaches to the English Reformation. Early writers, most notably John Strype, viewed the Reformation primarily as an event in political history; they collected and analyzed the documents which established the independent Church of England. Writing in 1936, Sir Maurice Powicke went so far as to say that “the one definite thing which can be said about the Reformation in England is that it was an act of State.” The classic modern account of Reformation politics is that by A. G. Dickens, first published in 1964. This approach remained dominant through the 1970s. Several of Sir Geoffrey Elton's magisterial works described the religious policies of Henry VIII's chief minister Thomas Cromwell, while the statutes passed by Henry VIII's parliaments to regulate religion were studied by Stanford Lehmberg in his books The Reformation Parliament and The Later Parliaments of Henry VIII. Biographies of Thomas Cranmer naturally emphasized the primary role of the archbishop of Canterbury in enforcing reforms.
Works of this sort see the Reformation as coming rapidly and being imposed from the top down. But another sort of historiography, gaining popularity in the 1980s, viewed Reformation as a slow process working its way up from the bottom as Lutheran, Zwinglian, and Calvinistic views gradually gained acceptance by common people. Another perspective on popular belief emphasized the reluctance of many men and women to abandon their traditional Catholic beliefs.
More than 36000 individuals living in rural Malawi were skin tested with antigens derived from 12 different species of environmental mycobacteria. Most were simultaneously tested with RT23 tuberculin, and all were followed up for both tuberculosis and leprosy incidence. Skin test results indicated widespread sensitivity to the environmental antigens, in particular to Mycobacterium scrofulaceum, M. intracellulare and one strain of M. fortuitum. Individuals with evidence of exposure to ‘fast growers’ (i.e. with induration to antigens from fast growers which exceeded their sensitivity to tuberculin), but not those exposed to ‘slow growers’, were at reduced risk of contracting both tuberculosis and leprosy, compared to individuals whose indurations to the environmental antigen were less than that to tuberculin. This evidence for cross protection from natural exposure to certain environmental mycobacteria may explain geographic distributions of mycobacterial disease and has important implications for the mechanisms and measurement of protection by mycobacterial vaccines.