Vortioxetine: Long and Short Term Effectiveness

Vortioxetine: Long and Short Term Effectiveness Clinical Efficacy and Tolerability Studies:  Effectiveness in short term therapy Thase M et al. performed meta-analysis on 10 short term placebo-controlled clinical trials [studies analyzed were with Clinical trial registry no:NCT00839423, NCT00635219, NCT00735709, NCT01140906, NCT01153009, NCT01163266, NCT00672958, NCT00672620, NCT01179516, NCT00811252]outcome submitted to USFDA for vortioxetine approval purpose and demonstrate the efficacy of the compound in treatment of MDD. They observed existence of dose response correlation across the dosage strength (5-20mg/day) of vortioxetine on the basis of MADRS as efficacy measurement scale. The analysis reported clinically meaningful efficacy of vortioxetine through mean difference in change from baseline MADRS total score (32.4 ±4.1 for vortioxetine(n=2416) and 32.1 ±4.0 for placebo(n=1439)) observed for 5mg strength(difference of change in score: -2.6; p=0.008), 10 mg strength (-3.5; p The very first study to identify efficacy, safety and tolerability of vortioxetine 5mg and 10 mg/day dosage vs. placebo was carried out for 6 weeks with participation of 429 patients with baseline Montgomery–Åsberg Depression Rating Scale (MADRS) total score 30. Venlafaxine XR 225mg/day was used as an active reference in this multi-site study. The study exhibited superior treatment by vortioxetine in comparison of placebo as evident by significant difference (p Impairment in health-related quality of life (HRQoL) is a chronic illness directly related to depression. Improvement in HRQoL in patient suffering of MDD reflects therapeutic effectiveness and enhance patient adherence to the drug. Florea I et al. performed random effect meta-analysis on 9 placebo controlled short term studies [Studies included are Clinical trial registry no.: NCT 00839423; NCT00635219; NCT01323478; NCT00672958; NCT00672620; NCT00735709; NCT01153009; NCT01163266] of patients with MDD receiving vortioxetine using a variety of quality-of-life assessment tools. The meta-analysis (FAS, MMRM) showed a statistically significant difference from placebo in favor of vortioxetine (p Effectiveness on Cognitive function: Efficacy of vortioxetine on cognitive function in depressed adults Memory impairment as a Neurocognitive mutilation is prominent in patients with MDD and the same is considered s a marker of brain dysfunctinality (Burt D). Antidepresant drugs with positive effect on reversal of cognitive dysfunction are differenciated from the antidepressants with no cognitive effect to facilitate good prescription in general. In a preclinical study, Vortioxetine enhanced memory in rat as evident by novel object recognition test and alleviated extracellular level of acetylcholine and histamine when 1-10 mg/kg drug is administered subcutaneously to experimental animals (Mork A, 2013). The chronic dietary administration of drug also found to be effective in alleviation of stress-induced impairment in reversal learning when adult male rats were exposed to chronic intermittent cold (CIC) stress and 4-chloro-DL-phenylalanine methyl ester hydrochloride (PCPA), a 5-HT depleting agent (Wallace A, 2014). Restoration of 5-HT depletion impaired memory by Vortioxetine was also demonstrated by Jardin KG and Jansen JB through PCPA induced 5-HT depletion model and behavioural tests including object recognition (OR) and Y-maze spontaneous alternation (SA) tests respectively. SERT (Serotonin transporters) occupancy (>90%) by vortioxetine was established in their preclinical work, with reports of dose-dependently reversed recognition memory and spatial working memory in rats. Effectiveness in MDD relapse prevention (Long term therapy) Major depressive disorder (MDD) patients have to maintain therapy even after remission by acute treatment to prevent relapse especially when residual symptom and comorbid illnesses (E.g: MDD with generalized anxiety disorder) are present at the remission point (Keller M, 2007). The long term efficacy of antidepressants is also be established by study of its role in maintenance treatment in preventing depression recurrence in patients who responded to acute therapy (Kornstein 2006)(Steinert C 2014). Alam M et al (NCT 00707980) carried out an open-label, 52-weeks, long term study to identify efficacy of vortioxetine along with monitoring of adverse effects. This was the extension of two double blind, placebo controlled short term (8weeks) lead in studies involving participants suffering of MDD. Total 834 patients were treated with 5 mg/day dose of vortioxetine for first week followed by dose titration from 2.5 mg/day to 10 mg/day depending on intensity of response till 52 weeks. The study concluded with absence of potential adverse effect reports and proved efficacy of vortioxetine by maintenance of remission observed by Change From Baseline score of MADRS Total Score (Observation: -7.4  ±9.81 units Change from baseline score as end point result) and 24-item Hamilton Depression total score (Observation: -7.9  ±9.66 units change from baseline score as end point result). Furthermore, Baldwin DS et al reported safety and efficacy of vortioxetine in prevention of relapse of MDD o n the basis of 52 weeks of remission maintenance therapy in patients who previously completed acute therapy of vortioxetine for 8 weeks with evidence of remission. Patients reported approximately 8 points reduction from 13.5 ±8.7 base line MADRS score after 52 weeks of treatment indicated favorable profile of vortioxetine (2.5, 5 and 10 mg/day) in relapse prevention during long term remission maintenance therapy of MDD. At the end of 52 week treatment, approximately 2% patients have shown sign of relapse (MDRS score ≠¥ 22) as per Montgomery-Asberg Depression Rating Scale. For vortioxetine, a MDD relapse prevention study was carried out with participation of 639 MDD patients aged between 18-75 years and diagnosed with a current major depressive episode (MDE) within four weeks duration. In this investigation, against baseline score in MADRS scale ≠¥26, a remission point was considered as MADRS total score ≠¤10 for vortioxetine (5 or 10 mg/day) treated patients to enter in double-blind, 24 weeks phase of treatment with either placebo (n=192) or vortioxetine (n=204) for relapse time analysis. At the end of the study, relapse rate was 13% and 26% for vortioxetine and placebo treated groups respectively as an evidence of efficacy of vortioxetine in prevention of relapse in 396 patients participated in 24 week phase (Boulenger JP 2012). COMPARATIVE EFFICIENCY Treatment with vortioxetine (2.5 mg, 5 mg, 10 mg) failed to make differentiation from placebo when Change From Baseline in MADRS Total Score was considered as a primary efficacy analysis tool in a 8 Week randomized, double blind clinical study. In the same investigation, Duloxetine (60 mg), a reference drug used to find efficacy of vortioxetine, also failed to make differentiation against placebo in primary efficacy analysis. Secondary efficacy outcome analysis and tolerability analysis suggested efficacy of vortioxetine with 5mg and 10 mg strength through MMRM (Mixed-Effect Model Repeated Measure) model (Badwin DS, 2012). In a randomized, double blind study involving comparison of vortioxetine (n= 252) and agomelatine (n=241), superiority of treatment with vortioxetine (p Katona C et al reported significantly (P = 0.0011) higher efficacy of vortioxetine (5 mg/day) in comparison of placebo by 24-item Hamilton Depression Scale (HAM-D (24)) total score () as the primary measure. 29.2 vs. 19.3% remission rate were observed at the endpoint for vortioxetine and placebo controlled population respectively during the study which also involved duloxetine as active reference. The patient adherence rate was 94.2% in case of vortioxetine and 90.1% in case of duloxetine demonstrated tolerability of vortioxetine in their study. Comparative Safety of vortioxetine (10mg per day) in MDD treatment was established on the basis of 15 days study demonstrating its effect on psychomotor performance in 24 healthy subjects. The drug didn’t show alteration in psychomotor functioning withing and at the end point of te study. The investigation also involved use of Mirtazapine as an active reference which was found to be inferior through strandardized driving test due to cognitive impairment obsrved by it. (Theunissen). EFFECTIVENESS ON ETHNIC POPULATION Majority of the clinical investigations listed in table 3 were carried out at multi sites involving global population and diverse demographic distribution. The drug was found to be equally effective on participants from different countries. Recently H.Lundbeck announced head-to-head study results comparing efficacy and tolerability of vortioxetine 10mg/day and venlafaxine XR 150mg/day in treatment of MDD in 437 adult participants (Inclusion criteria: MADRS total score ≠¥26) from four Asian countries, Thailand, South Korea, Taiwan and China. The end point outcome established slightly more effectiveness of vortioxetine compared to venlafaxine with mean difference of -1.20 points in change observed in baseline MADRS total score(with 95% CI: -3.03 to -0.63). The superiority of vortioxetine was strongly supported by its tolerability data observed as lesser incidences of adverse events (6.6% vs. 13.7%) and lesser drop out ratio of participants (18% vs. 27.4%) in case of vortioxetine treatment compared to active reference. Efficacy of vortioxetine in Asian population was established by substantial improvement in MDD as evident by change in baseline score i.e.: -19.4 points on MADRS total score. SAFETY AND TOLERABILITY Efficacy and safety for Sexual function maintenance Sexual dysfunction is one of the major risks of antidepressant therapy particularly with selective serotonin reuptake inhibitors (SSRIs)(Strohmaier J 2011). Therapy discontinuation is reported frequently in clinical studies involving various antidepressants due to adverse effects associated with sexual problems which includes including anorgasmia, problems in ejaculation, absence of libido and impotence but still sexual dysfunction is one of the most under-rated AEs (Serretti A). at the same time symptoms and illness of depression is also known to be associated with sexual dysfunctions(Baldwin D, 2013 AND Foong T; Reichenpfader U,). In this dilemma, the data generated through efficacy and safety studies of vortioxetine are supporting the selection of vortioxetine as an antidepressant with the minimum side effects as far as sexual health impairment is concerned. A study involving MDD patients suffering of SSRI monotherapy (Treatment with citalopram, paroxetine or sertraline) induced sexual dysfunction indicated effectiveness of vortioxetine in clinically meaningful improvement in sexual functioning compared to escitalopram. This multicentre, randomized, double-blind, active controlled clinical trial was carried out on SSRI treated 447 participants who were already in partial or full remission state from MDD as measured by the MADRS and CGI-S/I(Clinical global impression severity and improvement scales). The participants were switched 10 mg/day fixed dose of vortioxetine or escitalopram for the first week of study. Further, the dose was increased to 20 mg/day in second week followed by flexible dose (10-20 mg/day) till the end of 8th week. The dose was taped down to 10 mg/day for escitalopram control group whereas vortioxetine treated group was switched to placebo control for another 1 week. Treatment with vortioxetine(n=169) concluded in a s tatistically significant treatment effect by change from baseline CSFQ-14(Changes in sexual functioning Questionnaire) total score at the end of 8th week of study in comparison of escitalopram(n=179). A mean treatment difference of 2.2 points for vortioxetine vs escitalopram groups(95% CI: 0.48—4.02; p=0.013, MMRM) proved efficacy of vortioxetine in sexual function restoration and MDD remission mintenance in patients treated with other antidepressant previously. Previously, during the proof-of-concept, short term efficacy study for vortioxetine (5mg/day and 10 mg/day) with placebo control and active reference control has demonstrated statistically higher safety of vortioxetine in comparison of active reference (12.4% incidences for venlafaxine vs. 1.9% incidences for 5 mg/day vortioxetine and placebo, p=0.0033, Fishers exact test) and equivalent safety in comparison to placebo group for the incidences of sexual dysfunction related adverse effects. In contrast, Mahbaleshwarkar 2013 (NCT00672620) reported high incidences (51% for and 37.5% for vortioxetine 2.5 mg and 5 mg versus 26.9% duloxetine and 33.3% placebo group) of treatment-emergent sexual function impairment by treatment with vortioxetine. They monitored sexual dysfunction as a adverse effect using the ASEX (Arizona sexual experience) scale. The study involving a total 9f 611 participants also concluded with observation of non-significant difference in changes from baseline of HAM-D2 4 total score between 5mg, 10 mg vortioxetine and placebo. The above studies indicate that sexual function related AEs is not a concern for long term use of vortioxetine as a remission maintenance therapy unlike other antidepressants whereas patients may suffer by adverse effects related with sexual dysfunction when the therapy for remission with 5mg or 10 mg dose is started in patients suffering of MDD. Adverse Effects Frequency and severity of adverse effect and change in selected vital body parameters, ECG, weight change due to vortioxetine (2.5, 5.0 and 10.0mg/day) administration were observed during a 52 week open labeled study by during a open label long term study by Baldwin DS. They also considered physical examination and clinical safety laboratory tests to make thorough investigation. Out of 535 participants, only 2% of individuals have shown sign of severe adverse effects but none of the adverse effect was prevalent in more than 0.56% individuals among total participants. Apart from this, majority of the patients reported the non-serious adverse effects have shown sign of nausea (19.81%) and headache (15.33%). Sexual dysfunction related adverse effects were reported in six patients at the end of the study. This study was also concluded with effectiveness of vortioxetine in long term treatment as mentioned previously in this article. The study was concluded with positive outcome in terms o f tolerability of vortioxetine for long term maintenance therapy in patients with MDD remission. Drug Interactions Vortioxetine dose adjustment is not required based on age, race, gender, ethnicity, renal or hepatic impairment but due to serotonin syndrome and neuroleptic malignant syndrome, the drug is contraindicated in concomitant administration with irreversible non selective MAOIs(Monoamino oxidase inhibitors). Chen G et al reported drug interaction cases affecting pharmacokinetic profile of vortioxetine in healthy subjects. They observed need of dosage adjustment of vortioxetin when it is concomminately administered with bupropion, rifampicin as steady state AUC and Cmax of of vorteoxetine enhanced by 128 and 114% in case of bupropion co-administration and suppressed by 72% and 51% in case of rifampicin co-administration. At the same time, tolerability of simultaneous therapy was evident by absence of any severe adverse effects. They also reported safety of vorteoxetine in concomminent administration of popular contraceptive, Estradiol. Vortioxetine is mainly metabolized in liver by CYP2D6 and up to some extent by CYP2C9 and CYP34/5. This makes vortioxetine sensitive to other drugs which are CYP2D6 inhibitors, CYP3A4 and CYP2C9 inhibitors and Cytochrome P450 inducers. Other than these, reversible and non-selective MAOI and serotonergic medicinal products are also potential drug substances affecting efficacy and safety of vortioxetine.

Business Edge Email

To: David Johnson Subject: Information on Business Edge Dear Mr David Johnson Firstly I would like to thank you for your response to my email based on my application for the sales and marketing position you are currently have available. I am pleased to know you would like further knowledge of my completion of the Business Edge Program undertaken through my Bachelor of Business at Edith Cowan University. The program helped me develop a range of skills related to the sales and marketing role in which I have applied for. The following email will represent the key aspects that Business Edge specified within my time in the program. I will analyze the different components of Business Edge and the skills I have gained during the program. Additionally I will explain how these concepts will be beneficial to your company. As a result this email will give you background knowledge on my intake and understanding of the Program. The Business Edge program is designed to help students understand the growing impact of international competition in businesses and employment and how to successfully operate in the global marketplace. The program introduces students to the concept of business and to various interpersonal, group work and organizational skills essential for university and employment success. The Program is also geared to helping students to realize and improve their abilities in individual learning styles, group work, cross-cultural communication, business communication, critical thinking and ethical behavior. In addition, the Business Edge program introduces students to the concept of self-reflection, self-discovery, self- criticism, peer assessment and information and time management. Having completed this program I can tell you that it is an extremely unique course as it focuses on student centered learning. This means that there are plenty of role-plays, scenarios, interactive multi-media and activities where students develop their employability skills by ‘doing’. As the student you must use your previous knowledge and experience, apply these to real situations and learn from those around you so that your employability skills can be developed and refined along the entire length of the program. A key attribute I have developed through the Business Edge program is the â€Å"ability to communicate†. This gives me excellent employability skills such as forming effective relationships with customers and employees. This is a perfect attribute for the sales and marketing role. As someone interested in sales and marketing I think it is essential that you communicate effectively and form networks with customers and fellow clients. I think the ability to interact with others openly and objectively is vital criteria for the position and Business Edge has certainly given me a great advantage in this area. The main emphasis that the Business Edge program projected was on clear communication and presentations. Personally I feel to be a competent communicator you must first be able to listen and understand others, in particular with sales because face to face communication is frequent and also phone conversation. I think my ability to understand clear communication and my advanced understanding of open questions will benefit your company greatly. I know when working in sales and marketing you have to allow communication to flow and invite open discussion. You must have a clear tone as well as a good posture if talking to an audience, when talking on a phone your manner must be polite while still being clear and able to adapt. I believe that a good communicator is someone who can change the way they communicate to suit the person they are speaking to. You should express yourself in a way that makes sense to that person. I think the Business Edge program has helped me achieve this and it will be a great asset in the sales and marketing role. Another attribute that I developed through the Business Edge program is the â€Å"ability to work in teams†. The Business Edge program as stated earlier is student centered and the learning process is by â€Å"doing†. Most of this is done through group work, participating in various activities and presentations. Through these activities I could improve my self-confidence to a higher level. I got an idea about how to work in groups with mutual understanding and to respect others ideas as well. With the knowledge I gained from this unit, I’m now able to get others give their ears to me and express my ideas in an effective manner in front of an audience.

A report on the serious failures of winterbourne view Essay

Winterbourne View, and the company Castle Beck Care LTD, failed to protect the individuals in their care from various types of abuse. They were not protected adequately from harm, risk and the own unsafe practices of the staff employed there. Staff at Winterbourne View had failed in their legal duty to notify the Quality Care Commission of serious incidents, including injuries to patients and occasions when they had gone missing. see more:identify reports into serious failures to protect individuals from abuse Ten essential standards, which the law requires providers to meet and Winterbourne View did not include; The managers did not ensure that major incidents were reported to the CQC as required. Planning and delivery of care did not meet people’s individual needs. They did not have robust systems to assess and monitor the quality of services. They did not identify and manage risks relating to the health, welfare and safety of patients. They had not responded to or considered complaints and views of people about the service. Investigations into the conduct of staff were not robust and had not safeguarded people. They did not take reasonable steps to identify the possibility of abuse and prevent it before it occurred. They did not respond appropriately to allegations of abuse. They did not have arrangements in place to protect the people against unlawful or excessive use of restraint. They did not operate effective recruitment procedures or take appropriate steps in relation to per sons who were not fit to work in care settings. They failed in their responsibilities to provide appropriate training and supervision to staff. The CQC report concluded that there were systemic failures in protecting people or to investigate allegations of abuse. Footage used in prosecutions showed member of staff repeatedly assaulting and harshly restraining patients under chairs, giving patients cold punishment showers, with one patient being left out in near zero temperatures and another having mouthwash poured in their eyes. Members of staff also pulled hair, poked people in the eyes, force fed medication and mocked patients to the extent one actually tried to escape through a second floor window to escape the torment. These are all massive failings of the staff and the company to provide a safe and secure environment for its service users. The CQC was also guilty of failing to investigate claims thoroughly. The case of Winterbourne View and the coverage that Panorama aired on television shocked the nation. Undoubtedly making a lot of people question the capability of the CQC as well as their local homes / services, where family members or friends may visit or live. The CQC held an internal inquiry and as a result there were many changes to various organisations. Winterbourne view inevitably closed and eleven people plead guilty to criminal offences of neglect or abuse. Six of which were jailed.

Details of James Deans Death in a Car Accident

In September 1955, actor James Dean was driving his brand-new Porsche 550 Spyder to an auto rally in Salinas, California, when he was involved in a head-on collision with a 1950 Ford Tudor. James Dean, only 24 years old, died in the crash. Although already famous for his role in East of Eden, his death and the release of Rebel Without a Cause caused James Dean to soar to cult status. James Dean, forever frozen as the talented, misunderstood, rebellious youth remains the symbol of teenage angst. Who Was James Dean? John Kobal Foundation/Contributor/Getty Images James Dean had appeared in a number of television shows before getting his big break in 1954 when he was chosen to play Cal Trask, the leading male role in the film East of Eden (1955). This was the only one of Deans films released before his death. Quickly following East of Eden, James Dean was signed to play Jim Stark in Rebel Without a Cause (1955), the film for which Dean is best remembered. Immediately following the filming for Rebel Without a Cause, Dean played the lead role in Giant (1956). Both of these films were released after Deans death. James Dean Raced Cars As Deans movie career began to take off, James Dean also started to race cars. In March 1955 Dean raced in the Palm Springs Road Races, and in May of that year he raced in the Minter Field Bakersfield race and the Santa Barbara Road Races. James Dean liked to go fast. In September 1955 Dean replaced his white Porsche 356 Super Speedster with a new, silver Porsche 550 Spyder. Bettmann/Contributor/Getty Images Dean had the car specialized by having the number 130 painted on both the front and back. Also painted on the back of the car was Little Bastard, Deans nickname given to him by friend Bill Hickman, who was Deans dialogue coach for Giant. The Accident On September 30, 1955, James Dean was driving his new Porsche 550 Spyder to an auto rally in Salinas, California, when the fatal accident occurred. Originally planning to tow the Porsche to the rally, Dean changed his mind at the last minute and decided to drive the Porsche instead. Dean and Rolf Wuetherich, Deans mechanic, rode in the Porsche. Following were photographer Sanford Roth and Bill Hickman, driving a Ford station wagon that had a trailer for the Spyder attached. En route to Salinas, Dean was pulled over by police officers near Bakersfield for speeding around 3:30 p.m. After being stopped, Dean and Wuetherich continued on their way. Two hours later, around 5:30 p.m., they were driving westbound on Highway 466 (now called State Route 46), when a 1950 Ford Tudor pulled out in front of them. 23-year-old Donald Turnupseed, the driver of the Ford Tudor, had been traveling east on Highway 466 and was attempting to make a left turn onto Highway 41. Unfortunately, Turnupseed had already started to make his turn before he saw the Porsche traveling quickly toward him. Without time to turn, the two cars smashed nearly head-on. The injuries among the three involved in the crash varied greatly. Turnupseed only received minor injuries from the accident. Rolf Wuetherich, the passenger in the Porsche, was lucky to be thrown from the Porsche. Although he suffered serious head injuries and a broken leg, he survived the crash. Dean, however, was killed in the accident. Dean was just 24 years old at the time of the wreck. Posthumous Academy Awards To this day, James Dean is the only person to receive two Academy Award nominations posthumously. In 1956, he was nominated posthumously for Best Leading Actor for his role in East of Eden. This was a historic first. In 1957, Dean was again posthumously nominated for Best Leading Actor, this time for his role in Giant. What Happened to Deans Smashed Car? Many Dean fans wonder what happened to the smashed Porsche. After the accident, the crumpled car was toured around the United States as part of a driver safety presentation. However, en route between two stops, the car disappeared. In 2005, Volo Auto Museum in Volo, Illinois, offered $1 million to anyone who currently had the car. So far, the car has not resurfaced.