Qantas Emphasizes On Achieving Vision Marketing Essay

Qantas Emphasizes On Achieving Vision Marketing moveQantas Airways special was established in 1920 in Queensland, Australia. It is the largest that escape valve both(prenominal)(prenominal) internal and global destination as surface as oldest skyway in Australia. In the past, Qantas started sending mails and autorying travelers by biplanes and expand the destinations worldwide such(prenominal) as Australia, Asia, The Americas, Europe, and Africa. Qantas departs the wide-cut overhaul for passengers who shoot both external and home(prenominal).Qantas emphasizes on achieving the slew and the goals to be the triader in flight path labor. Qantas is a agio, across-the-board supporter air duct which way on the base hit world-class, mange airplane that suit adequate to(p) with the destination, c ar about node service, operative transactionively, and crap two s tumescenessful defects paper that is Qantas and Jetstar. Jetstar is subsidiary of Qantas which c ondenseing on the low appeal. The caller-up likewise contacts for represent advantage and differentiate.Qantas applies Porters Five Forces of Michael Porter to spot persistence structure. Regarding to airline business assiduity is deregulation Qantas is the private airline line of credit that independence from government. thereof on that straits atomic number 18 many a(prenominal) competitors compete with low monetary value and give birth to survive the node loyalty. This report also analyze Qantass item with dweeb that is Strengths, Weaknesses, Opportunities, and Threats. The federation is sorting at the substance competencies to be different from the competitors and taking attain from the cost advantage by victimization strategies to ground up combative advantages and crisscross knowledge and defect loyalty. To obtain the brand image and client loyalty, the caller-up pauperisation to concern about guest service by creating the promotion such as make bail bond with prestigious in game spirits society both external and local. Moreover, Qantas need to provide much(prenominal) readying to the round to act with passengers that move create node fealty.Qantass corporate missionThe Qantas Airways Limited has the mission teaching to achieve the purpose of them as the best airline of the world. According to Aviation business sector (2009) stated that The corporate mission statement for the 2008/09 FY was restoring our report card, confronting the crisis, operating sustainably and planning for the future. To achieve the vision of Qantas group which include Qantas Airways and Jetstar, they focus on on the five chemical elements such as guard duty is branch antecedence, providing the aircraft to duo with the right routes, fling the best guest services, operational effectiveness, and two strong complementary brands both Qantas and Jetstar. (Aviation business, 2009 Qantas Airways, 2010) head start factor is guard fi rst. Qantas is the premium that provide wide-service both global and local airline. (Qantas Airways Limited, 2010) They manage and unchanged the best sentry duty by exercising and reporting the safety to be the worlds best safety airline. (Qantas Airways Limited, 2010) Second, providing the aircraft to suit the route, Qantas foc intents on renovate the aircraft to be competent as compound up as match with the direction. (Qantas Airways Limited, 2010) For example, Qantas Group arranges for 50 Boeing 787s to revamp their aircraft to match with network. (AAP, 2010) Third, offering full client services, the best customer service is the basis of their objective. (Qantas Airways Limited, 2010) Forth, operational effectiveness, Qantas on decides to action by straight shipness as intumesce as create productivity through their familiarity. (Qantas Airways Limited, 2010) Last, making strong brand both Qantas and Jetstar, the conjunction endeavors to create the best premium brand for Qantas and Jetstar as low cost. (Qantas Airways Limited, 2010)Qantass argument Strategies associate to Qantass corporate mission the company applies the business dodge to accomplish their mission which emphasize on several things such as forward thinking, safety first, sustainable operations, strong reputation brands, great hoi polloi, pukka pedestal, feel for customers, environmental responsibility, and giving feed bet on. (Qantas yearbook Review, 2010) In addition, Qantas focuses on all types of business strategy such as cost go alongership and differentiate however the company emphasize on differentiate from clean(prenominal) airlines.First strategy is forward thinking. Qantas has been undertaking the innovation of technology to be uplifteder mathematical process and be the subscribeer of product and service in airline business. (Qantas annual Review, 2010) The company also uses this strategy to be a part of their horticulture as puff uphead as the innovation i s always considered about their customers assume and shareholders need. (Qantas yearly Review, 2010)Second is safety first. It is one of the strategies that Qantas concerns. rubber eraser first is the spunk of their company due to the company take to be the best safety procreation and reporting of the world. (Qantas Annual Review, 2010) Qantas focuses on flying safety, safety management, security, occupational health and safety, and performance. (Qantas Annual Review, 2010) Qantas invests amount of money to reassert high meter of operational safety and performance. (Qantas Annual Review, 2010) All ply safety training is overseen by policy that bothone is able to show the safety through singular act and effectively management risk. (Qantas Annual Review, 2010) Moreover, the Qantas groups occupational Health and Safety (OHS) program provide useful system such as health and safe work surrounding and strong safety culture to validate the company to avoid harm. (Qantas Annual Review, 2010)Third, this is sustainable operations. According to The Qantas Group Annual Review (2010) mentioned that For the Qantas Group, sustainability is about managing short- line and long-term risks, seizing opportunity, and doing things right for our shareholders, our customers, our people and our community.Forth, Qantas focuses on strong brand reputation. As Qantas is the main airline of Australia, the company is the premium transporter that provide the full service both international and internal route with safety. (Qantas Annual Review, 2010) there are two keys factor that Qantas concerns such as exactly time and faithfully to tint customer satisfaction as well as the company still attempt to preserve with high performance standards. (Qantas Annual Review, 2010)Fifth, Qantas concerns for the great people both men and women to work with excellent place as well as offer training and improvement their staffs skill. (Qantas Annual Review, 2010) For example, the company inve sts in alter leadership skills for managers to operate staff to meet everyone satisfy. (Qantas Annual Review, 2010)Sixth, superordinate word infrastructure is one of Qantass business strategies. To success in flight, it is essential to invest to restore the aircraft for developing in safety, travelers comfort, costs, render efficiency, noise, emanation, freight capacity, and range capability. (Qantas Annual Review, 2010) Moreover, creating superior infrastructure, Qantas also concerns for engineer science due to it is one of factors that build Qantas reputation for security, trustworthy, and production. (Qantas Annual Review, 2010) In addition, Qantas is also concerning about the catering that serve to passenger both international and domestic as well. (Qantas Annual Review, 2010) What is more, the airport is one of the superior infrastructures that the company concerns due to the firm cares for high forest of terminal and lounges facilities to support passenger who transfer t he flight. (Qantas Annual Review, 2010)Seventh, Qantas does everything to meet customers need from booking and embarkation and from in flight to suit casefuls collection. (Qantas Annual Review, 2010) The company provides to assists the travelers what they want as well as caring for safety, happiness, and convenient. (Qantas Annual Review, 2010) For example, Qantas offers the next generation check in which include seat selection, online and mobile check-in, kiosks, and premium service desk and security. (Qantas Annual Review, 2010)Eighth, environmental responsibility, Qantas is always considering for the environmental strategy by emphasizing on fuel preservation as well as supporting the environmental organizations throughout the Qantas Foundation. (Qantas Annual Review, 2010)Last, giving feedback is one of Qantass business strategies that works as tie to encourage, offer opportunities, save the surrounding and assist mostthing that suffer from catastrophe. (Qantas Annual Review, 2010) In addition, Qantas is also supporting and be sponsor for sports such as convening 1and football World Cup 2022. (Qantas Annual Review, 2010) What is more, the company is giving back for the society and families that support them from abroad. (Qantas Annual Review, 2010)Industry structureIn term of labor structure, the essay is analyzing with Porters five forces with current situation of airline industry. Qantas caller Limited is an example to examine for the industry structure. The company set up describe with industry rivalry, potential sweet entrants, substitutes, suppliers, and buyers.First of all is industry rivalry. In the past, Australian Airline market is regulating by government provided in 1990 it changed to deregulation so Qantas acquired local Australian Airline and being the market leader. (Flight Global, 2010) However, there are many competitors that had occurred in the airline industry after deregulation that evict compete with Qantas. then this industr y is high competition and low risk due to rate of return and high cost as well as airline industry corporation face with the big problem such as sparing crisis. (Investopedia, 2010) Therefore Qantas confronts with high industry rivalry that existing in the airline industry especially international airline. Air Asia, for instance, it is the low cost airline that flight across Southeast Asia and Australia. (Thomas, 2010) Consequence, there are many competitors that existing in the market at the present it can continue growingd in the future as well.Second, potential new entrants is one of the current situation of industry structure that Qantas has to concern. As airline industry need to use large amount of money to enter in this industry so it is quite difficult for the new investors to invest. (Investopedia, 2010) Moreover, it is depending on the financial situation as well. (Investopedia, 2010) However, if the new airliners can create the company reputation, they can easily to t rip the customers even the price are higher. (Investopedia, 2010) Therefore the potential new entrants are somewhat high in the airline industry be front of deregulation as well.Third, substitutes, airline industry hand over high competition as well as a cost is also high. (Investopedia, 2010) For the domestic, travelers can take car or train or bus instead of utilize airline service that can effect with airline industry. (Investopedia, 2010) However, some passengers who use international flight can a little effect with airline industry due to they do not have more choice to go abroad. (Investopedia, 2010) Therefore the substitutes may high or low, it is depending on the customers favorite such as convenient, budget, and time. (Investopedia, 2010)Forth, bargain power of suppliers is one of forces that can analyze the business strategy. Airbus and Boeing are primarily supply the aircraft for airlines business. (Investopedia, 2010) For example, overall of aircrafts of Qantas is ap proximate 246 aircraft which including Boeing 747s, 767s,737s and 717s, Airbus A380s, A330s and A320s, Bombardier Dash 8s and Bombardier Q400s. (Qantas Airways Limited, 2010) As mentioned for Qantass aircraft, it is can see that most of fleets are supplying by Boeing and Airbus. Therefore the bargaining power of suppliers is high in current airline industry.Last, bargaining power of buyers, as Qantas is the premium, full service in-flight both international and domestic airline. (Qantas Annual Review, 2010) The company had focused on the customer satisfaction. (Qantas Annual Review, 2010) There are high price if the passenger p look up to change the airplanes merely the airline can compete with the service such as comfortable. (Investopedia, 2010) On the other hand, as the current situation customers have many options such as buy ticket via travel agent, or website itself to choose, they may concern for price, quality and service. Therefore the bargaining power of buyers is high f or the airline industry.SWOT AnalysisSWOT analysis uses for evaluating the strategy of the company which can take off into 2 parts such as external and internal environment. impertinent analysis is looking at the Opportunities and Threats outside the organization as well as Internal analysis is emphasizing on the Strengths and Weaknesses within organization. (Value ground Management, 2010)External Analysis (Opportunities and Threats)OpportunitiesTechnology advance, Qantas uses the technology to apply with products and service for customer to have more convenient. For example, according to Tay (2010) A 2D barcode image is replacement paper boarding passes for domestic passengers using Qantass new Mobile sign in service. This service provide customers check in on their mobile which they forget receive text message confirmation with 2D barcode. (Tay, 2010) Moreover, Jetstar also leave behind launch this system as well. (Tay, 2010) In addition, as Qantas is one of the members of Oneworld alliance that is big alliance group. This group can lead Qantas has many services for example, Frequent vizor program can create brand cognizance and customer loyalty for Qantas. (Qantas, n.d.)ThreatsThere are many threats that can come to with Qantas current situation such as fuel price, economic crisis, environmental problem and deregulation. Nowadays, fuel price is unstable and trend to increase, it is the problem that every airline worry. According to ABC News (2008) mentioned that Qantas CEO Geoff Dixon says fuel prices are a greater challenge to the global airline industry than severe acute respiratory syndrome or the September 11, 2001 terrorist attacks in the US. In term of economic crisis, it can bear on with airline business revenue that passenger use less(prenominal) of travel by airplane due to high cost. Moreover, environmental problem, refer to a volcanic explosion in Iceland it can affect with Qantas stop flight and wooings of delay. It can lead to disap point for passengers who have to wait at the airport. (AAP, 2010) Moreover, deregulation of airline industry can effect with Qantas. Deregulation playacts up the airline focuses on complete in low cost instead of service and safety. ( ask Finds, 2010)Internal Analysis (Strengths and Weaknesses)StrengthsQantas Airways Limited has strong business strategy with full service and premium as well as Jetstar focuses on the low cost fare. (Qantas Airways Limited, 2010) The company has high strong brand recognition and brand reputation which receive the award for the best premium economic assort. (Qantas Airways Limited, 2010 Platt, 2010)) The company also emphasize on the best safety and customer service. Moreover, Qantas is one of the members of Oneworld shackle which include the big airline such as American Airlines, British Airways, Canadian Airlines and Cathay Pacific. (Study Finds, 2010) The purpose of this group is part each other within the group such as engineering and performan ce as well as provides many facilities to passenger when connecting flight. (Study Finds, 2010)WeaknessesRefer to Qantas manages the merciful resources especially engineering and maintenance from overseas. It can escape of able and knowledge of staff to maintain the aircraft. (Study Finds, 2010) It also can damage the brand image and customer loyalty. In addition, the company provides inadequate training of staff. Moreover, Qantas is unable(p) to control their staff. (Harvey, 2009 Bourke, 2010) As Qantas focuses on the safety first, everyday flight 24 hours even holiday but their engineers strike for holiday that can effect with them. (Harvey, 2009 Bourke, 2010)Core CompetenciesIn term of core competencies, it is necessary for the business to bring the business strategies with the warlike advantage to apply in the business process. (Value ground Management, 2010 Matt, 2010) Those competencies can develop the end products more efficiency as well as core competency consist of ab ilities of acquaintance, production process, customer relationships and staff which garter the company to reach the goal and being the market leader. (Vitez, 2009)Moreover, strategic architecture can describe the possible ways that the company is able to go to future and bring the company go along the new core competencies to create the benefits as well as reach the customers need and provide them to use those benefits efficiently. (Hamel and Prahalad, 1994, p.118) Strategic architecture such as reading and social architecture is the ways to define the top managements to allocate the human resources correctly. (Hamel and Prahalad, 1994, p. 117) For example, According to Hamel and Prahalad (1994, p. 117) stated that To create a social architecture elder management must have a point of view on what values should predominate, what behaviors should be encouraged, what kind of people should feel comfortable working(a) in the company.In case of Qantas, Airways Limited, the companys co re competency is premium airline with full services. The company applies their core competencies with two strong brands reputation both Qantas and Jetstar and human resources. What is more, Qantas Airways Limited puts core competencies to create the firm to have free-enterprise(a) advantages.Competitive advantageRefer to Michael Porters private-enterprise(a) advantage is called generic strategies that have 3 main areas such as cost leadership, differentiate and focus or niche strategy. (Marketing Teacher, 2010 Matt, 2009) Focus group can divide into 2 parts namely cost focus and differentiate focus which look within focus market. (Value Based Management, 2010 Mind Tools, n.d.)Refer to Qantas Airways Limited, the company emphasizes on differentiate and cost advantage to reach competitive advantage. Hence, Qantas Airways Limited concerns competitive advantage which looking at the differentiate advantage and cost advantage. class AdvantageAccording to Investing Smart (n.d.) pointed o ut that Jetstars quick rise to be one of the worlds most successful low-cost carriers places the Qantas Group well in term of product offering and differentiate. A380s and B787 Dreamliners, for instance, Qantas organizes to book those 2 aircrafts to serve the passenger to compete the competitive advantage more than others. (Investing Smart, n.d.)In case of Qantas establishes the frequent posting program that different from other airline to make customer loyalty. (Qantas, n.d) According to Hoffman (2010) stated that Qantas announced today that Qantas Frequent Flyer has reached seven million members and predicted ongoing solid growth over the foreseeable future. The purpose of this program is to motivate passenger travel by using Qantas. The benefit of using frequent flyer, they will get point to shape up the seat if earn enough point or using point in some alliance store and upgrade for weight of baggage as well as accessing to the Oneworld alliance lounge which provide foods, drin ks, and other facilities. (Qantas, n.d. Hoffman, 2010) Moreover, Qantas is also coalition with many local companies such as supermarket, eating place entertainment, travel travel services, finance and business and shopping car. Woolworths, for example, Qantas uses frequent flyer program to associate with Woolworths Everyday Rewards to gather the point which provide the competitive advantage to each other. (Evan, 2010 Hoffman, 2010) salute advantageRefer to Qantas Airways Limited is the premium full airline service with the premium price. The company starts the Jetstar for low cost airline to serve the passengers who travel in domestic such as Sydney and Melbourne. (Qantas Airways Limited, 2010) Moreover, as Qantas is one of the world recognition and reputation brand with the full service and safety in the airline industry. Qantas is also pushing Jetstar to flight for global destination in Asia Pacific to serve travelers to get more option as good service as Qantas with the econo mical fare. (Gregg, 2007) system RecommendationsAs Qantas Airways Limited have plausible business strategies that can lead their business successful. Nevertheless, the company also has some weaknesses can cause many problems. Consequently, Qantas should pursue some recommendation to sustain the brand recognition and reputation.Cost and competitionRegarding to airline industry is deregulation which independence from the government. It can lead to the intense of competition in case of cost. Airlines can freedom to set the price and some have less quality. Thence, the government should re-deregulation for airline industry. (Lowy, 2010 Elliott, 2010 Study Finds, 2010) This can avoid the airline competition with the lower cost and maintain the good quality of customer services as well. (Lowy, 2010 Elliott, 2010 Study Finds, 2010) Moreover, it also helps to renew the financial situation of airline industry as well as brand recognition. (Elliott, 2010). In addition Re-deregulation can decr ease the new competitors to cut the costs as well. (Elliott, 2010)Customer ServicesAs airline industry is both products and services that provide customers and reach the best satisfaction. Alliance is one of the ways that can provide the passengers happy. Qantas should collaborate with both domestic and global company. Metro Hotel, for example, the hotel is the partner of Qantas Frequent Flyer program when the customers using the frequent flyer card with this hotel they will get the point that can convert to be the money or voucher or throw out from some events. (Metro Hotel, 2010) It is not only hotel but also car rental, market place store, and bank. (Credit Card Finder, 2010) This way can make both companies get the customer loyalty and motivate them to use their service. Moreover, Qantas should make survey to update the exposit what customers want such as service, catering, seat, entertainment, flight attendant, and lounge. (Platt, 2010) This theme can help Qantas to maintai n the rank of the worlds best airline, sustain customers pleasure, and retain the profit of the company as well. (Platt, 2010) In addition, Qantas should not focus only the first class but also economy class as well. To reach customer satisfaction, the company should provide and serve all class with the best service such as meals, seat, and drinks. (Govindasamy, 2010)Human ResourcesQantas should focus to human resources by providing more training to meet customers fulfillment as well as brand recognition. The company put facilities and urge for staffs training to meet the standard of customer service and reach customers satisfaction. (Creedy, 2009) In addition, the company should encourage staff to be a part of their business as well. Moreover, safety is one of the first priorities that every airline must concern. Qantas Airways Limited, for example, as airline industry is high risk, the company needs to maintain the standard of safety. It is because of if the company lack of safety and security it can be in trouble that can cause damage of brand recognition and reputation. (Sykes, 2010) Qantas should invest to hire the best engineering to preserve the objective of the company. If the company provides the best wellbeing and security, it can build up the brand image and profit as well. (Sykes, 2010) Moreover, Qantas should provide reliableness to all customers and employee as well as manage the environmental neighborly in the areas. (Sykes, 2010 Qantas Airways Limited, 2008)Potential FalloutRegarding to Qantas Airways Limited achieves the vision and goals of company itself and be the best premium with full service airline. Anyway, the company can meet some failures. Hence, the company needs to keep their firm going and maintain the financial situation stable in the present and future as well. The potential fallout can include human resources and re-deregulation that Qantas should be worried.First of all, Qantas may be unsuccessful due to the human resources. R efer to Qantass goals, the company concerns for the safety first. The company has to invest large amount of money to training and hire outsourcing staff especially engineering and maintenance but they are unqualified. (The Daily Telegraph, 2008) Qantas can fail due to their staff are lack of attention and participate to maintain the good quality of engine as well as some of them lack of knowledge that can cause of accidents. (The Daily Telegraph, 2008) For example, Qantass aircraft faces the accident due to the inadequate of employee to check properly. (Study Finds, 2010) Moreover, from some study found that Qantass training such as emergency evacuations and baggage manipulation fail. (ABC News, 2010) Therefore refer to worlds best airline rank Qantas had dropped. (Platt, 2010) It can lead Qantas damage of brand reputation as well as customer loyalty.Re-deregulation can be one of failures that airline industry may face. As deregulation allows the airline set the cost by them, it ca n increase the intense of competition in low cost. Regarding to Qantas focuses on the premium and full airline service moreover they also focus on Jetstar as a low cost airline. If the authorities restore the re-deregulation, it may affect with Qantas and Jetstar. It is because the government may control the price and the standard of service. When the passenger needs to travel in domestic, they may change the behavior to use other modes such as cars, train or bus that because of high cost of air ticket (Study Finds, 2009) Refer Jetstar may affect due to they focus in low fare ticket, it can reduce the profit of the company. purposeQantas Airways Limited has strong brand reputation in the premium and full service airline with a subsidiary Jetstar as the low cost airline. They provide great the products and services for passenger and create the brand reputation in the global. The company also stresses on the advance technology, safety is first priorities, customer services, environmen tally friendly and human resources. Besides they apply their strategies and core competencies to reach customers want and build up customer loyalty.Anyway, there is some threatening such as domestic and international competition that can lead Qantas weaken. Those contestants can snatch the market share and create brand loyalty by better service, less accident, and punctual. Thus, Qantas has to maintain standard the quality of service to be the worlds best airline in the world.

Analysis of SAMe as an Antidepressant

Analysis of akin as an AntidepressantS-Adenosyl-Methionine ( equal) And meliorate Methylation advance A Serious Alternative To Orthodox MedicationsCan S-Adenosyl-Methionine ( equivalent) and improve methyl meetingation carry a serious alternative to orthodox musics in the intercession of printing?AbstractIn this dissertation we think the tax returns surrounding the apply of similar as an antidepressant drug. in that location be roughly(prenominal) an(prenominal) a(prenominal) diverse aspects to this con officeration.We fasten on by a involveation of exactly what busted-down gear is on a clinical basis and probe the psychological and physiological changes that characterize the condition. We thusly consider and examine the phylobrokersis of the current resiles of antidepressant medicinal drug.We explore the field of neurochemisattempt and pathophysiology of depressive says with cross emphasis on the chemistry of the methylation re achieve and its relevance to the similar compound. esteem is then given to very(prenominal) specific in all(a)y as a medication and the evidence that in that location is to choke its app bent beneficial tack in embossment. This is then expanded with a carriage back of the chemistry of said(prenominal) and its inter fol clinical depression ups with ear prevaricationst(a) biologically bustling entities.We conclude the exploration with a hypercritical review of the published books that is relevant to the economic consumption of alike(p) as an antidepressant agent.IntroductionIn revision to investigate the full finale of the oral sex at the heart of this dissertation we mustiness examine a spot of background issues in whatever detail frontmost. Depression is a entangled clinical asseverate. It has been said that thither atomic make sense 18 as m whatever(prenominal) theories close to the etiology and treat manpowerts for first gear as there argon clinicians thought su ffice astir(predicate) the job. (LeDoux, J. 1996). A draft examination of the literature on the issuing tells us that this none, although distinctly in beed to be flippant, whitethorn not in reality be so very ut slightly from the truth.Perhaps it is be baffle of the plethora of hypotheses, ideas and theories on the issue that there argon alike a consider up to(p) repress of tenors of handling that atomic physical body 18 jetplacely employed. It has to be admitted that several(prenominal) argon rational and any(prenominal) command to be completely irrational. In this dissertation we shall examine to a great extent or less of the much than rational unionizes of psychopharmacology in order to understand the key of said(prenominal) in the therapeutic pharmacopoeia.Depression is a comm scarce go a hugering illness. It leave behind signifi weedtly affect between 10-25% of women and approximately half that snatch of men during their carriagetimes. ro und 5 million mint in the UK get out sustain signifi nett falloff in any given year. (Breggin 1994)If you fall back from an slap-up or degenerative illness you argon scour more(prenominal) believably to suffer from depressive states with frequencies ranging from 30-50% depending upon the nature and severity of the illness. (Robertson et al 1997)What is economic crisis ? in that location are many definitions of clinical economic crisis and and so many different judge scales which aspire to try to quantify it. It is primary(prenominal) to distinguish between clinical operation and simply feeling down or miserable. Depressive illness typically fades in episodes although in more or less cases it fecesister in reality last for many months or even years. (Skolnick, P. 1999). wholeness severe depressive episode is a major(ip) single-handed risk itemor for getting further episodes. In new(prenominal) words, having had effect once you are statistically considera bly more probable to do an opposite attack. (Post RM. 1992).For our purposes we shall consider a practical overview of the nine unequivocal symptoms that characterise classical depression1. Depressed sense modality for rise(p)-nigh of the daylight2. strike inclination or change in weight3. disgusted pile4. Psychomotor retardation or tempestuousness5. Loss of s features in previously pleasurable activities unfitness to enjoy usual hobbies or activities6. moil or loss of energy7. Feelings of worth littleness excessive and/or unbefitting guilt8. Difficulty in concentrating or thinking distinctly9. pathological or suicidal thoughts or fol down(p) outs.(After Zuess 2003)The Diagnostic and Statistical manual of arms of moral Disorders (DSM-IV) states that in order to merit a diagnosis of clinical depression you need to demonstrate at least five of these symptoms and that they guard a change in your life.Mood alterations are commonplace in depressive states. The glo omy diligent will classically feel despair or sadness. joyfulness becomes an alien emotion as they tend to progressively out of ca-ca affair in activities that they would bring forth previously enjoyed. Mood swings behind as well hail although they are more usually imbed in bipolar states (manic depression). immanent feelings of tension or irrit office are often set forth as well as just sadness. (Duman et al 1997)In amplification to mood changes, depression dirty dog likewise produce changes in the excited state as well. Feelings of worthlessness and guilt are perhaps the comm angiotensin- win overing enzymest emotions in the clinical spectrum. This is closely followed by twain ineptitude and neediness of self-assertion in virtuosos own abilities or capabilities. It is common for blue people to shoot down action that avoids them having to take responsibility because of an overwhelming fear of failure. (Altar CA 1999) corporeal manifestations of depression are p erhaps easier to quantify as they bugger off a qualitative characteristic rough them as conflicting to the purely subjective. Changes in appetite are usually be. handsomely it is an anorexic change with a mitigate in appetite and a loss of interest in fodder comm lone(prenominal). Less frequently, the converse is observed with a voracious add in appetite (comfort eating) which is prevalently associated with weight gain. This weight gain rout out be quite substantial in extreme cases.Sleep disturbances are commonplace. Insomnia and early waking are perhaps the comm unmatchablest of this type of symptom. This burn occur contempt severe subjective symptoms of somatic tiredness and fatigue. nigh people will come that fatigue is a prominent symptom and whitethorn think that this is translated into excessive sleeping and motor retardation frequently.Fatigue is actually more difficult to quantify, moreover it is commonly experienced by the depressed patient. It can eithe r be an overwhelming tiredness (lack of energy) or perhaps lack of stamina (tiring too easily). Associated with this is often a reduction in libido and, if severe, impotency can alike occur. It is not odd to find informal avoidance demeanors developing in these circumstances. (Janicak et al 1989)Concentration is commonly impaired. Generally harangue the greater the degree of depression, the greater is the degree of concentration impairment. cerebration and abstract thought affectes slow down and the attention span is often markedly reduced. Students find they can hold back an inability to select and if severe, patients report an inability to even sit and watch television. (Bazin et al 1994)Somatic symptoms can occur without the psychological elements of the depression being apparent or obvious. This is a common clinical dilemma. Patients whitethorn enter a phase of denial or minimization where they will not accept that they are actually depressed. They can try to ration alise their physical symptomatology into otherwise disease processes. This can be ill-advised for hypochondriasis. (De Vanna et al 1992)If depression is severe (or occasionally part of a symptom difficult of another(prenominal) underlying pathology), then psychosis can be prime. neurotic states are not uncommon in severe depression. Hallucinations can occur, only if they are comparatively unusual. Patients can state that they hear voices rotund them that they are worthless or perhaps instructing them to kill themselves. Although this is consistent with a depressive diagnosis, one should note that other illnesses much(prenominal)(prenominal)(prenominal) as schizophrenia must distinctly be considered and excluded before a confident diagnosis of depression can be made.The actual basis or specific triggering featureors for depression are not yet clearly defined tho we do k straight off that a physical body of different biological dotors are relevant. environmental factors, in concert with both transmissible and neurobiological elements are all confident of influencing the general clinical picture. (Kendler KS, 1998).Depression is broadly divided into endogenous and antiphonal types. In general damage endogenous depression is thought to be influenced the genetic and neurobiological factors whereas re quick depression may well stick out environmental factors as being relevant. This has considerable implications in our considerations of the viable actions of aforementioned(prenominal). (Gold et al 1988) pharmacology of depressionThis is a vast subject and is by and large considered to be a sub-speciality in its own right. It has long been recognised that certain substances wait to be able to exert a mood elevating do. The advent of modern font psychopharmacology allowed us to develop an understanding into just how some of these substances stimulate. The drugs and medicines that are in common use today are the authority out of a process of e volution that, arguably, began with the uses of herbs at the stemma of recorded history and progressed to the chemical substancely and biologically advanced compounds that are in use today. (Peinell and Smith 2003)In order to displace the alike compounds into their appropriate place in the continuum we need to discover at some of the evolutionary increments in the field.Most of the currently utilize antidepressants process by interfering in some way with the actions of the dissimilar neurotransmitters in the brain. Many give out by slowing down the biological processes of abasement or destruction of these neurotransmitters. In purely simplistic price, this solvings in a greater concentration of the neurotransmitter at the critical synaptic interfaces inwardly the brain. (Levine et al 1998)The first real break with with(predicate) with what could be considered to be a major therapeutic agent for depressive states came with the stripping of the monoamine oxidase inhibit or (Monoamine Oxidse Inhibitors), gathering of drugs. 3 were commonly utilise in clinical practice isocarboxazid, phemelzine and tranlcypromine. For a firearm they were utilise extensively solely it became obvious that they had serious drawbacks including some potentially disgraceful side pictures. (Saarelainen et al 2003),Headaches dizziness and tremor were not unusual accompaniments of the drug. They withal had the ability to move with other medications and certain types of food (tyrosine containing foods such as cheese could cause hypertensive crises). patronage these drawbacks, many patients were willing to take them because they indisputably worked. (Skolnick 1999)In time, the MAOis were superseded by the Tricyclic gathering of drugs. There were quatern in common use, namely amitriptyline, desipramine, imipramine and nortriptyline. These were generally speaking, marginally more legal than the MAOIs yet they were without the worst of the side cause. Despite that, they were still able to cause dry let the cat out of the bag and blurred vision in some people. harm and drowsiness were not unusual and they were not commonly used if a person as well had hypertension. The pharmaceutical industry then produced a number of different categories of medication in fairly quick succession.SSRIs (Selective serotonin re-uptake Inhibitors), SNRIs (Serotonin and norepinephrine reuptake inhibitors) and NDRIs (Norepinephrine and dopamine reuptake inhibitors) all emerged into the grocery store place. (Smith et al 2004)It is probably fair to say that they all had their niches in the therapeutic spectrum however the SSRIs were go outn to corner the biggest share of the clinical market with citalopram, escitalopram, fluoxetine, paroxetine and sertraline as examples of the sort. fluoxetine hydrocholoride was probably the most(prenominal) widely used and its trade name, fluoxetine hydrocholoride was accredited almost as a household word.The side effect v isibleness of this event group was certainly less probative than their predecessors, merely malady and headaches were not uncommon. (Stewart et al 2000),The SNRIs fell into disuse braggyly because of their theme in raising cholesterol levels and the NDRIs were base to cause unacceptable agitation in certain groups.There was then an emergence of a group of drugs which not only blocked the instruments that removed the trophic neurotransmitters from the synapse they as well as had an effect which efficaciously enhanced their action by blocking the action of the repressive neurotransmitters at the comparable time. There are several types of medication in this category, barely perhaps the best cognise is maprotilene. Like most of the other types of telling medication, it is not without side personal effect. Drowsiness, nausea, dizziness and a dry mouth are common accompanying symptoms of a therapeutic dose of this medication. (Harmer et al 2003)Neurochemistry and pathoph ysiology of depressionSo far we save take a brief and admittedly comparatively simplistic tour of the nature and pharmacology of depression. We shall now olfactory modality at the neurochemistry and pathophysiology of certain relevant aspects of the subject in more detail.In general terms, test and antidepressants depend to eat reciprocal actions on neuronic growth and to some extent, on their legal action (see on). This come forwards to be with the intermediation of various neurotrophins and the action of synaptic plasticity mainly in the field of the genus Hippocampus and some other brain structures (Reid et al 2001). conglomerate stresses appear to disturb and disrupt the activity, both of individual neurones and besides bigger working(a) groups, or networks of neurones whereas antidepressants appear to antagonise this disruptive ability. (Henke 1990) There is a large body of opinion which agrees with the transcription that regulation of synaptic activity is a ma jor key to the pathophysiology of depression and related complaints. (Drevets et al 1997)The baring of the MAOI group of drugs (above) led researchers to speculate that the monoamine group of neurotransmitters were rally to the aetiology of depression. As more research is done it is becoming apparent that this may not actually be the case. It is now considered more apt(predicate) that the native problems lie further along the metabolous cascade from the monoamine oxidase activity. It is also considered belike that the pathology may well not be just a chemical imbalance, but may well involve other functions of neural wander such as various cellular changes in physiology, genetic factors and the ability of neuronal network to change their characteristics. (Czyrak et al 1992)Observational studies micturate suggested that early life experiences, the impact of stress and the presence or absence of tender support or interactions all have an influence on the development of a depre ssive state. (Gould et al 1998).Consideration of the monoamine chemistry clearly does not account for all of these factors although it is clearly ac hit the sackledged that it does play an important contributory piece.Some upstart work relating to the chronic use of different classes of antidepressants (Duman et al 1997), has appeared to show that they all are able to improver the production of the neuroprotective groups of proteins which, amongst other actions, play a commutation image in the plasticity of neurones. Current thinking is that this may well be a common function of a number of different pathways that the different antidepressants exploit.It is cognize that enlarges in monoamine levels in the synaptic theatrical role result (by a number of different mechanisms) and are associated with the induction of enzyme systems that reign gene reflectivity within the neurone. This can be inferred from the finding of cast ups in the levels of messenger RNA which codes for the cAMP response element binding protein (CREB). These levels slowly increase with chronicity of administration of antidepressants and this mechanism may well account then for the commonly observed slow and progressive onset of action of most of the antidepressant drugs.It is proposed that CREB triggers the production of BDNF (Brain Derived Neurotrophic Factor). This is significant since other work has shown that stress antagonises the levels of BDNF which is opposed by the actions of the antidepressant drugs. (Smith et al 1995). Further credence is given to this possible action with the discovery that placing BDNF directly into the brain of experimental animals appeared to relieve many of the behaviour patterns that are associated with depression (Siuciak et al 1997)Some authors have suggested that depression may take on a oddly subtle form of neural chronic disorder as it has been shown that the genus Hippocampus becomes progressively atrophic in chronic depressive states. This is particularly significant as BDNF is thought to reverse such findings. (Shah et al 1998). There is associated supporting evidence in the form of a hold by Vaidya (et al 1999) which shows that ECT sermon (which was forever assumed to be bad to the neural structure and physiology) is associated with both increased levels of BDNF and trophic changes in the hippocampal neurones.A paper by Czyrak (et al 1992) looked at the antidepressant activity of homogeneous in mice and rats in a way that clearly is not possible in humans. It is not always possible to directly understand findings from animals to humans, but there are some pieces of evidence in this work which strongly implicate same in the pathogenesis of depression. The paper itself is extremely long and complex but the relevant parts to our considerations here are the fact that normal geographical exploratory behaviour in rodents tends to minify if a depressive state is induced. To some extent, exploratory behaviour is then considered a patsy for the depressive state. It was raise that uniform tended to increase exploratory activity in mice. This, and other more sophisticated testing of the pharmacological interactions of SAMe showed that it tended to have the same psychopharmacological profile as many of the mainstream antidepressants.Many of the neurotransmitters and for that matter some neuroactive hormones have been variously involve in the aetiology of depression (eg thyroid hormones and noradrenaline). (Nemeroff, 1998). new-fangled research has most consistently prime that alterations in the levels of serotonin (5-HT) (Melzter H, 1989), system and the chemicals of the Limbic Hypothalamic-Pituitary-Adrenal (LHPA) axis of rotation. (Kathol et al 1989), as the most consistently implicated mechanisms that appear to be associated with the control of the mood stabilising and regulating mechanisms. It is in fact very plausibly that both these mechanisms are in some way interlinked as part of the regulatory mechanism of mood.We have already have in mindred to the role of stress in the aetiology of depression. We recognize that the adrenal glucocorticoid hormones subtly interact with the 5-HT system and these are produced in direct response to stress. (Lopez et al 1999) (I). We also know that the glucocorticoids have a number of direct effects on the Limbic Hypothalamic-Pituitary-Adrenal (LHPA) axis. It may be that this is the mechanism by which stress antagonises the changes brought about by SAMe. (Lopez et al 1999) (II)We do not need to consider the effects of the corticoids on the LHPA axis in detail as it is only of peripheral device relevance to our considerations here. The important consideration in this regard is that the LHPA axis is most connected to the hippocampus. It is this structure that is the intermediate step and connection between the bodys hormonal response to stress and the response of the mellower functions of the brain. (Dallman et al 198 7).The prompt relevance of all this to the actions of SAMe are that hyperactivity of both the hippocampus and the LHPA axis are both well documented in cases of clinical depression. This has been shown to also be associated with high levels of corticosteroid production (Kalin et al 1987), but one study has shown that in suicide cases who have had profound depression the hippocampus has few corticosteroid receptor sites than one index normally expect (Lopez et al 1998).One further piece of clinical evidence in the role of the corticosteroids in depression is that patients with Cushings disease have a high relative incidence of depression. This incidence returns to normal when their hormonal over-activity is treated and returned back to physiological levels. (Murphy 1991)SAMe as a medicationSAMe was discovered in Italy in 1952 during research into the chemistry of neurotransmitters. It was not, however, introduced in a useable form for patient well-being until 1974 (as SAMe sulph ate-paratoluene-sulphonate). It is for this reason that the majority of the early papers and work on the subject are almost exclusively Italian in origin. (De Vanna et al 1992)SAMe has been used clinically in a number of conditions including cholestasis, osteoarthritis and depression. (Carney et al 1987) Although there is a wealth of literature on the first two elements it is not relevant to our considerations here. We shall therefore dress this discussion to the spectrum of its use in the field of depression.A number of studies have shown that SAMe has useful activity in depressive illness. Studies that have compared it to placebo have found that it can consistently produce about a 6 school principal increase on the Hamilton rating scale after about three weeks of optimum treatment. This finding is approximately in line with the results that are found with most of the other clinically effective antidepressant medications. (Cooper et al 1999) (De Vanna et al 1992)Some studies ha ve found that using SAMe in a large dose has produced an unusually rapid onset of beneficial effects (Kagan 1990)One could argue that, because it is a naturally occurring substance, it would not be likely to have a high side-effect profile. Although these two statements do not always follow, it is generally true. A study by Bressa (1994) on the issue showed that it did have a particularly low side-effect profile, particularly when compared to the other antidepressants (Tricyclics). To demonstrate this turn on further, we can point to the study by Caruso (et al 1987) where there were a greater number of patient withdrawals due to the side effects of the placebo than withdrew because of the SAMe drug. For the record, that particular rivulet was in its use as an antiarthritic rather than an antidepressant, but the point is made.The two major unwanted clinical effects are nausea and hypomania. The nausea is not a local effect on the catgut lining but appears to be a centrally negoti ate effect and is maybe caused by the same phenomenon of over-stimulation of the neuronal networks which causes the other major clinical manifestation of hypomania. For this reason it is generally not used in cases of bipolar disorder. (De Vanna et al 1992)It is probably not strictly accurate to refer to SAMe as a drug as it is normally found in the cellular matrix.It has been found to be effective in patients who have been otiose to tolerate other forms of antidepressants or, for that matter, have had minimal response to them.(Reynolds et al, 1984) boylike (1993) produced a particularly interest review of dietary treatments for depression. A muss of his article is not relevant to our considerations here, but he makes a number of interesting and relevant observations. Low serotonin levels are known to be associated with depression even though low levels on their own do not appear to cause the condition. It appears that it needs to be in gang with a low level of folic acid. We k now that low levels of folic acid are also often found in combination with depressive illness and that low levels of vitamin M are often associated with low levels of SAMe. The evidence points to the fact that the low levels of serotonin are more likely to be a result of the low SAMe levels in neural tissue and that this is more likely to be nearer to the root of the main anomaly that causes depression.Pregnancy is known to be associated with low levels of folate and post natal depression is a well recognised clinical entity. Salmaggi (et al 1993) considered the effects of SAMe in the postpartum period. This was a well considered and constructed study. It was a double blind placebo controlled outpouring over a 30 day period and had an entry age group of 80 women. The degree of depression was assessed before, during and after the tribulation on the Hamilton Scale. The results showed a statistically significant improvement in the SAMe group when compared to the placebo group. The a uthors comment that there were no significant side effects of the medication encountered.Because we know that any beneficial effect that SAMe is likely to have on a patient tends to be seen more quickly than with the other antidepressants, and also, by justice of what we suspect about its probable mode of action in the hippocampus and elsewhere in the brain, it seems a logical step for mortal to look into the effects of giving SAMe alongside a unoriginal antidepressants to see if there is either any synergistic effect or possibly a speeding up of the clinical onset of the secondary winding medication.The study by Berlanga (et al 1992) did exactly that. Unfortunately the trial was not particularly rigorous in its design as although it was double blind, it was not placebo controlled, which would appear to have been the method of choice in this type of investigation. Its other problem as that it only had an entry cohort of 40 patients. Despite these limitations it was indeed shown t hat depressed patients who took SAMe in conjunction with other antidepressant medication found that the depressive symptoms resolved faster with the SAMe added to their normal treatment regime.There are one or two other less important papers which we shall only mention in passing. Kagan (et al 1990) ran a low-pitched trial on 15 inpatients (with very severe depression) and found SAMe to be a safe, effective antidepressant with few side effects and a rapid onset of action. This particular trial is noteworthy as it was the first to report the side effect of mania in a patient who didnt have a previous history.Another is the trial by Rosenbaum (et al 1990). This particular trial is notable for the demonstration of the fact that about 20% of other treatment resistant patients experienced benefit with SAMe.Faya (et al 1990) (II) considered the fact that SAMe is thought to exert its effect through its action in increasing dopamine levels in the synaptic cleft. It is known that dopamine inhibits the production of both Thyroid stimulating hormone (TSH) and prolactin from the hypophysis gland. Faya considered measuring the levels of both TSH and lactogenic hormone during treatment with SAMe. His findings comprise something of a surprise insofar as in the men in the trial group had their levels of TSH and Prolactin reduced which is consistent with the hypothesis that SAMe increases the dopamine levels in the brain. Much to everybodys surprise, this effect was not seen in the effeminate group. The authors do not offer any explanation of this fact.For the record, there is another trial (Thomas et al 1987), which obviously considered the same phenomenon and their trial did not show any sex linked difference in the crushing of the Prolactin levelsWith regards to efficacy, a trial by Carney (et al 1986) suggests that the beneficial action of SAMe is restricted to endogenous depression and it does not appear to have any action above placebo on reactive depression. As f ar as we can ascertain, this is the only trial published that has made this suggestion, although from a first principles basis, one can see the biochemical rationale for accept that it might well be the case.On a purely trial-and-error grounds, some authors have recommended (on the basis of scant hard evidence), that SAMes action can be maximised by the addition of B12, B6 and folic acid. It is known that SAMe is required to convert these agents into their active form as a coenzyme. (Morrison et al, 1996). The same author also recommends the co-occurrent adminstration of Trimethylglycine (TMG) which is needful for the intracellular conversion of methionine into SAMe by the readiness of the necessary methyl- groups. Comment has to be made that again, this appears to be a completely experiential (and logical) suggestion, but we cannot find any hard evidence to stick out its clinical use.ChemistrySAMe is a basic component of cellular biochemistry. It occurs in every living cell and is second in enormousness only to ATP in both the number variety and moment of the reactions in which it serves as a cofactor. (Stramentinoli 1987).It is central in the chemistry of the transmethylation reactions. In substance its cellular function is to transfer the active methyl group form carrier molecules to a multitude of other molecules. In general terms, this methylation makes sluggish molecules biologically active.In addition to the transmethylation reactions it also plays a central role in transsulfuration and aminopropylation reactionsIt is tortuous in the synthesis of proteins including the nucleic acids, fatty acids, lipids and phospholipids, porphyrins and polysaccharides. In terms of our considerations here, perhaps the most significant reaction type that SAMe is composite in is the generation of the neurotransmitter amines. In this regard it is considered to be the most biologically significant provider of methyl groups within the cell. (Baldessarini 1987). S ignificantly it is also involved in the pathways to produce a number of other neurologically active compounds such as adrenaline, the neuronutrients acetyl l-carnitine and phosphatidyl choline (Mathews et al 1990)It is also to be found in the metabolic pathways of both serotonin and dopamine. Oral administration has been shown to increase the metabolites of these compounds in the CSF (implying increased turnover). It is thought to exert its antidepressive effect partly through the mechanism of increasing the levels of both dopamine and serotonin as neurotransmitters, but it also appears to have some form of trophic action on some of the neurones in the brain cortex. (Baldessarini 1987)It has been demonstrated that the tissue levels of SAMe tend to diminish with age and blood levels are also found to be low in some cases of clinical depression(Baldessarini 1987)A methyl group (CH3) is a group of three hydrogen atoms bound to one speed of light atom. It does not exist in a stable in sulate form and is transported between molecules by intermediaries such as SAMe. Methylation is the process by which this group is transferred from the methyl donor molecule to the recipient molecule.In general terms this process is central to the control of many of the intracellular pathways. large-minded a methyl group to an enzyme is often the key to activating it, and thereby beginning a synthesis or degradation process elsewhere in the cell. Equally removing the methyl group will render the enzyme lazy and fall apart that particular pathway. Similar mechanisms are involved in the expression of genes and therefore the production of proteins within the cell.Some specific methylation reactions include the methylation of phenols which withdraw them and thereby aid in their excretion. (Stramentinoli 1987)In the context of this dissertation, methylation is also central to the metabolic chemistry of serotonin (and therefore also melatonin). The activity of both these compounds is in effect regulated by the presence of a methyl group.SAMe is synthesised from methionine, a naturally occurring amino acid. As the name implies (METH-ionine), it contains a methyl group. By utilising the energy supplied by ATP and in the presence of magnesium, it is converted into SAMe. The process is catalysed by the intervention of the enzyme MAT (methionine adenosylAnalysis of SAMe as an AntidepressantAnalysis of SAMe as an AntidepressantS-Adenosyl-Methionine (SAMe) And Improved Methylation Offer A Serious Alternative To Orthodox MedicationsCan S-Adenosyl-Methionine (SAMe) and improved methylation offer a serious alternative to orthodox medications in the treatment of depression?AbstractIn this dissertation we consider the issues surrounding the use of SAMe as an antidepressant. There are many different aspects to this consideration.We start by a consideration of exactly what depression is on a clinical basis and examine the psychological and physiological changes that character ise the condition. We then consider and examine the evolution of the current forms of antidepressant medication.We explore the fields of neurochemistry and pathophysiology of depressive states with particular emphasis on the chemistry of the methylation reaction and its relevance to the SAMe compound.Consideration is then given to SAMe specifically as a medication and the evidence that there is to support its apparent beneficial effect in depression. This is then expanded with a review of the chemistry of SAMe and its interactions with other biologically active entities.We conclude the exploration with a critical review of the published literature that is relevant to the role of SAMe as an antidepressant agent.IntroductionIn order to investigate the full extent of the question at the heart of this dissertation we must examine a number of background issues in some detail first. Depression is a complex clinical state. It has been said that there are as many theories about the aetiolog y and treatments for depression as there are clinicians thinking about the problem. (LeDoux, J. 1996). A brief examination of the literature on the subject tells us that this comment, although clearly intended to be flippant, may not actually be so very far from the truth.Perhaps it is because of the plethora of hypotheses, ideas and theories on the issue that there are also a considerable number of forms of treatment that are commonly employed. It has to be admitted that some are rational and some appear to be completely irrational. In this dissertation we shall examine some of the more rational forms of psychopharmacology in order to understand the place of SAMe in the therapeutic pharmacopoeia.Depression is a commonly occurring illness. It will significantly affect between 10-25% of women and approximately half that number of men during their lifetimes. Approximately 5 million people in the UK will experience significant depression in any given year. (Breggin 1994)If you suffer from an acute or chronic illness you are even more likely to suffer from depressive states with frequencies ranging from 30-50% depending upon the nature and severity of the illness. (Robertson et al 1997)What is depression ?There are many definitions of clinical depression and indeed many different rating scales which purport to try to quantify it. It is important to distinguish between clinical depression and simply feeling down or miserable. Depressive illness typically occurs in episodes although in some cases it can actually last for many months or even years. (Skolnick, P. 1999). One severe depressive episode is a major independent risk factor for getting further episodes. In other words, having had depression once you are statistically considerably more likely to have another attack. (Post RM. 1992).For our purposes we shall consider a practical overview of the nine classic symptoms that characterise classical depression1. Depressed mood for most of the day2. Disturbed appeti te or change in weight3. Disturbed sleep4. Psychomotor retardation or agitation5. Loss of interest in previously pleasurable activities inability to enjoy usual hobbies or activities6. Fatigue or loss of energy7. Feelings of worthlessness excessive and/or inappropriate guilt8. Difficulty in concentrating or thinking clearly9. Morbid or suicidal thoughts or actions.(After Zuess 2003)The Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) states that in order to merit a diagnosis of clinical depression you need to demonstrate at least five of these symptoms and that they represent a change in your life.Mood alterations are commonplace in depressive states. The depressed patient will classically feel despair or sadness. Pleasure becomes an alien emotion as they tend to progressively loose interest in activities that they would have previously enjoyed. Mood swings can also occur although they are more commonly found in bipolar states (manic depression). Subjective feelings of tension or irritability are often described as well as just sadness. (Duman et al 1997)In addition to mood changes, depression can also produce changes in the emotional state as well. Feelings of worthlessness and guilt are perhaps the commonest emotions in the clinical spectrum. This is closely followed by both ineptitude and lack of confidence in ones own abilities or capabilities. It is common for depressed people to take action that avoids them having to take responsibility because of an overwhelming fear of failure. (Altar CA 1999)Somatic manifestations of depression are perhaps easier to quantify as they have a qualitative characteristic about them as opposed to the purely subjective. Changes in appetite are commonly found. Generally it is an anorexic change with a decrease in appetite and a loss of interest in food generally. Less frequently, the converse is observed with a voracious increase in appetite (comfort eating) which is normally associated with weight gain. This we ight gain can be quite substantial in extreme cases.Sleep disturbances are commonplace. Insomnia and early waking are perhaps the commonest of this type of symptom. This can occur despite severe subjective symptoms of somatic tiredness and fatigue. Some people will find that fatigue is a prominent symptom and may find that this is translated into excessive sleeping and motor retardation generally.Fatigue is actually more difficult to quantify, but it is commonly experienced by the depressed patient. It can either be an overwhelming tiredness (lack of energy) or perhaps lack of stamina (tiring too easily). Associated with this is often a reduction in libido and, if severe, impotence can also occur. It is not unusual to find sexual avoidance behaviours developing in these circumstances. (Janicak et al 1989)Concentration is commonly impaired. Generally speaking the greater the degree of depression, the greater is the degree of concentration impairment. Thinking and reasoning processes slow down and the attention span is often markedly reduced. Students find they can have an inability to study and if severe, patients report an inability to even sit and watch television. (Bazin et al 1994)Somatic symptoms can occur without the psychological elements of the depression being apparent or obvious. This is a common clinical dilemma. Patients may enter a phase of denial or minimisation where they will not accept that they are actually depressed. They can try to rationalise their physical symptomatology into other disease processes. This can be mistaken for hypochondriasis. (De Vanna et al 1992)If depression is severe (or occasionally part of a symptom complex of another underlying pathology), then psychosis can be found. Delusional states are not uncommon in severe depression. Hallucinations can occur, but they are comparatively unusual. Patients can state that they hear voices telling them that they are worthless or perhaps instructing them to kill themselves. Although this is consistent with a depressive diagnosis, one should note that other illnesses such as schizophrenia must clearly be considered and excluded before a confident diagnosis of depression can be made.The actual basis or specific triggering factors for depression are not yet clearly defined but we do know that a number of different biological factors are relevant. Environmental factors, together with both genetic and neurobiological elements are all capable of influencing the overall clinical picture. (Kendler KS, 1998).Depression is broadly divided into endogenous and reactive types. In general terms endogenous depression is thought to be influenced the genetic and neurobiological factors whereas reactive depression may well have environmental factors as being relevant. This has considerable implications in our considerations of the possible actions of SAMe. (Gold et al 1988)Pharmacology of depressionThis is a vast subject and is generally considered to be a sub-speciality in its own right. It has long been recognised that certain substances appear to be able to exert a mood elevating effect. The advent of modern psychopharmacology allowed us to develop an understanding into just how some of these substances work. The drugs and medicines that are in common use today are the result of a process of evolution that, arguably, began with the uses of herbs at the beginning of recorded history and progressed to the chemically and biologically sophisticated compounds that are in use today. (Peinell and Smith 2003)In order to put the SAMe compounds into their appropriate place in the continuum we need to look at some of the evolutionary developments in the field.Most of the currently used antidepressants work by interfering in some way with the actions of the various neurotransmitters in the brain. Many work by slowing down the biological processes of degradation or destruction of these neurotransmitters. In purely simplistic terms, this results in a greater concentr ation of the neurotransmitter at the critical synaptic interfaces within the brain. (Levine et al 1998)The first real breakthrough with what could be considered to be a major therapeutic agent for depressive states came with the discovery of the MAOI (Monoamine Oxidse Inhibitors), group of drugs. Three were commonly used in clinical practice isocarboxazid, phemelzine and tranlcypromine. For a while they were used extensively but it became obvious that they had serious drawbacks including some potentially fatal side effects. (Saarelainen et al 2003),Headaches dizziness and tremor were not unusual accompaniments of the drug. They also had the ability to interact with other medications and certain types of food (tyrosine containing foods such as cheese could cause hypertensive crises). Despite these drawbacks, many patients were willing to take them because they indisputably worked. (Skolnick 1999)In time, the MAOis were superseded by the Tricyclic group of drugs. There were four in c ommon use, namely amitriptyline, desipramine, imipramine and nortriptyline. These were generally speaking, marginally more effective than the MAOIs but they were without the worst of the side effects. Despite that, they were still able to cause dry mouth and blurred vision in some people. Constipation and drowsiness were not unusual and they were not commonly used if a person also had hypertension. The pharmaceutical industry then produced a number of different categories of medication in fairly quick succession.SSRIs (Selective Serotonin Reuptake Inhibitors), SNRIs (Serotonin and norepinephrine reuptake inhibitors) and NDRIs (Norepinephrine and dopamine reuptake inhibitors) all emerged into the market place. (Smith et al 2004)It is probably fair to say that they all had their niches in the therapeutic spectrum but the SSRIs were seen to corner the biggest share of the clinical market with citalopram, escitalopram, fluoxetine, paroxetine and sertraline as examples of the group. Fluo xetine was probably the most widely used and its trade name, Prozac was accepted almost as a household word.The side effect profile of this particular group was certainly less significant than their predecessors, but nausea and headaches were not uncommon. (Stewart et al 2000),The SNRIs fell into disuse largely because of their reputation in raising cholesterol levels and the NDRIs were found to cause unacceptable agitation in certain groups.There was then an emergence of a group of drugs which not only blocked the mechanisms that removed the trophic neurotransmitters from the synapse they also had an effect which effectively enhanced their action by blocking the action of the inhibitory neurotransmitters at the same time. There are several types of medication in this category, but perhaps the best known is maprotilene. Like most of the other types of effective medication, it is not without side effects. Drowsiness, nausea, dizziness and a dry mouth are common accompanying symptoms of a therapeutic dose of this medication. (Harmer et al 2003)Neurochemistry and pathophysiology of depressionSo far we have take a brief and admittedly comparatively simplistic tour of the nature and pharmacology of depression. We shall now look at the neurochemistry and pathophysiology of certain relevant aspects of the subject in more detail.In general terms, stress and antidepressants appear to have reciprocal actions on neuronal growth and to some extent, on their activity (see on). This appears to be through the mediation of various neurotrophins and the action of synaptic plasticity mainly in the region of the hippocampus and some other brain structures (Reid et al 2001).Various stresses appear to disturb and disrupt the activity, both of individual neurones and also larger functional groups, or networks of neurones whereas antidepressants appear to antagonise this disruptive ability. (Henke 1990) There is a large body of opinion which agrees with the hypothesis that regulatio n of synaptic activity is a major key to the pathophysiology of depression and related disorders. (Drevets et al 1997)The discovery of the MAOI group of drugs (above) led researchers to speculate that the monoamine group of neurotransmitters were central to the aetiology of depression. As more research is done it is becoming apparent that this may not actually be the case. It is now considered more likely that the fundamental problems lie further along the metabolic cascade from the monoamine oxidase activity. It is also considered likely that the pathology may well not be just a chemical imbalance, but may well involve other functions of neural tissue such as various cellular changes in physiology, genetic factors and the ability of neuronal network to change their characteristics. (Czyrak et al 1992)Observational studies have suggested that early life experiences, the impact of stress and the presence or absence of social support or interactions all have an influence on the develo pment of a depressive state. (Gould et al 1998).Consideration of the monoamine chemistry clearly does not account for all of these factors although it is clearly acknowledged that it does play an important contributory role.Some recent work relating to the chronic use of different classes of antidepressants (Duman et al 1997), has appeared to show that they all are able to increase the production of the neuroprotective groups of proteins which, amongst other actions, play a central role in the plasticity of neurones. Current thinking is that this may well be a common function of a number of different pathways that the different antidepressants exploit.It is known that increases in monoamine levels in the synaptic region result (by a number of different mechanisms) and are associated with the induction of enzyme systems that control gene expression within the neurone. This can be inferred from the finding of increases in the levels of messenger RNA which codes for the cAMP response e lement binding protein (CREB). These levels slowly increase with chronicity of administration of antidepressants and this mechanism may well account therefore for the commonly observed slow and progressive onset of action of most of the antidepressant drugs.It is proposed that CREB triggers the production of BDNF (Brain Derived Neurotrophic Factor). This is significant since other work has shown that stress antagonises the levels of BDNF which is opposed by the actions of the antidepressant drugs. (Smith et al 1995). Further credence is given to this theory with the discovery that placing BDNF directly into the brain of experimental animals appeared to relieve many of the behaviour patterns that are associated with depression (Siuciak et al 1997)Some authors have suggested that depression may represent a particularly subtle form of neural degenerative disorder as it has been shown that the hippocampus becomes progressively atrophic in chronic depressive states. This is particularly significant as BDNF is thought to reverse such findings. (Shah et al 1998). There is associated supporting evidence in the form of a study by Vaidya (et al 1999) which shows that ECT treatment (which was always assumed to be detrimental to the neural structure and physiology) is associated with both increased levels of BDNF and trophic changes in the hippocampal neurones.A paper by Czyrak (et al 1992) looked at the antidepressant activity of SAMe in mice and rats in a way that clearly is not possible in humans. It is not always possible to directly extrapolate findings from animals to humans, but there are some pieces of evidence in this work which strongly implicate SAMe in the pathogenesis of depression. The paper itself is extremely long and complex but the relevant parts to our considerations here are the fact that normal geographical exploratory behaviour in rodents tends to diminish if a depressive state is induced. To some extent, exploratory behaviour is therefore considered a marker for the depressive state. It was found that SAMe tended to increase exploratory activity in mice. This, and other more sophisticated testing of the pharmacological interactions of SAMe showed that it tended to have the same psychopharmacological profile as many of the mainstream antidepressants.Many of the neurotransmitters and for that matter some neuroactive hormones have been variously implicated in the aetiology of depression (eg thyroid hormones and noradrenaline). (Nemeroff, 1998). Modern research has most consistently found that alterations in the levels of serotonin (5-HT) (Melzter H, 1989), system and the chemicals of the Limbic Hypothalamic-Pituitary-Adrenal (LHPA) axis. (Kathol et al 1989), as the most consistently implicated mechanisms that appear to be associated with the control of the mood stabilising and regulating mechanisms. It is in fact very likely that both these mechanisms are in some way interlinked as part of the regulatory mechanism of mood.We have already referred to the role of stress in the aetiology of depression. We know that the adrenal glucocorticoid hormones subtly interact with the 5-HT system and these are produced in direct response to stress. (Lopez et al 1999) (I). We also know that the glucocorticoids have a number of direct effects on the Limbic Hypothalamic-Pituitary-Adrenal (LHPA) axis. It may be that this is the mechanism by which stress antagonises the changes brought about by SAMe. (Lopez et al 1999) (II)We do not need to consider the effects of the corticoids on the LHPA axis in detail as it is only of peripheral relevance to our considerations here. The important consideration in this regard is that the LHPA axis is intimately connected to the hippocampus. It is this structure that is the intermediate step and connection between the bodys hormonal response to stress and the response of the higher functions of the brain. (Dallman et al 1987).The immediate relevance of all this to the actions of SAMe are t hat hyperactivity of both the hippocampus and the LHPA axis are both well documented in cases of clinical depression. This has been shown to also be associated with high levels of corticosteroid production (Kalin et al 1987), but one study has shown that in suicide cases who have had profound depression the hippocampus has fewer corticosteroid receptor sites than one might normally expect (Lopez et al 1998).One further piece of clinical evidence in the role of the corticosteroids in depression is that patients with Cushings disease have a high incidence of depression. This incidence returns to normal when their hormonal over-activity is treated and returned back to physiological levels. (Murphy 1991)SAMe as a medicationSAMe was discovered in Italy in 1952 during research into the chemistry of neurotransmitters. It was not, however, introduced in a useable form for patient benefit until 1974 (as SAMe sulphate-paratoluene-sulphonate). It is for this reason that the majority of the ear ly papers and work on the subject are almost exclusively Italian in origin. (De Vanna et al 1992)SAMe has been used clinically in a number of conditions including cholestasis, osteoarthritis and depression. (Carney et al 1987) Although there is a wealth of literature on the first two elements it is not relevant to our considerations here. We shall therefore restrict this discussion to the spectrum of its use in the field of depression.A number of studies have shown that SAMe has useful activity in depressive illness. Studies that have compared it to placebo have found that it can consistently produce about a 6 point increase on the Hamilton rating scale after about three weeks of optimum treatment. This finding is approximately in line with the results that are found with most of the other clinically effective antidepressant medications. (Cooper et al 1999) (De Vanna et al 1992)Some studies have found that using SAMe in a large dose has produced an unusually rapid onset of beneficia l effects (Kagan 1990)One could argue that, because it is a naturally occurring substance, it would not be likely to have a high side-effect profile. Although these two statements do not always follow, it is generally true. A study by Bressa (1994) on the issue showed that it did have a particularly low side-effect profile, particularly when compared to the other antidepressants (Tricyclics). To demonstrate this point further, we can point to the study by Caruso (et al 1987) where there were a greater number of patient withdrawals due to the side effects of the placebo than withdrew because of the SAMe drug. For the record, that particular trial was in its use as an antiarthritic rather than an antidepressant, but the point is made.The two major unwanted clinical effects are nausea and hypomania. The nausea is not a local effect on the gut lining but appears to be a centrally mediated effect and is possibly caused by the same phenomenon of over-stimulation of the neuronal networks w hich causes the other major clinical manifestation of hypomania. For this reason it is generally not used in cases of bipolar disorder. (De Vanna et al 1992)It is probably not strictly accurate to refer to SAMe as a drug as it is normally found in the cellular matrix.It has been found to be effective in patients who have been unable to tolerate other forms of antidepressants or, for that matter, have had minimal response to them.(Reynolds et al, 1984)Young (1993) produced a particularly interesting review of dietary treatments for depression. A lot of his article is not relevant to our considerations here, but he makes a number of interesting and relevant observations. Low serotonin levels are known to be associated with depression even though low levels on their own do not appear to cause the condition. It appears that it needs to be in combination with a low level of folic acid. We know that low levels of folic acid are also often found in combination with depressive illness and t hat low levels of folate are often associated with low levels of SAMe. The evidence points to the fact that the low levels of serotonin are more likely to be a result of the low SAMe levels in neural tissue and that this is more likely to be nearer to the root of the main anomaly that causes depression.Pregnancy is known to be associated with low levels of folate and post natal depression is a well recognised clinical entity. Salmaggi (et al 1993) considered the effects of SAMe in the postnatal period. This was a well considered and constructed study. It was a double blind placebo controlled trial over a 30 day period and had an entry cohort of 80 women. The degree of depression was assessed before, during and after the trial on the Hamilton Scale. The results showed a statistically significant improvement in the SAMe group when compared to the placebo group. The authors comment that there were no significant side effects of the medication encountered.Because we know that any benefi cial effect that SAMe is likely to have on a patient tends to be seen more quickly than with the other antidepressants, and also, by virtue of what we suspect about its probable mode of action in the hippocampus and elsewhere in the brain, it seems a logical step for someone to look into the effects of giving SAMe alongside a conventional antidepressants to see if there is either any synergistic effect or possibly a speeding up of the clinical onset of the secondary medication.The study by Berlanga (et al 1992) did exactly that. Unfortunately the trial was not particularly rigorous in its design as although it was double blind, it was not placebo controlled, which would appear to have been the method of choice in this type of investigation. Its other problem as that it only had an entry cohort of 40 patients. Despite these limitations it was indeed shown that depressed patients who took SAMe in conjunction with other antidepressant medication found that the depressive symptoms resol ved faster with the SAMe added to their normal treatment regime.There are one or two other less important papers which we shall only mention in passing. Kagan (et al 1990) ran a small trial on 15 inpatients (with very severe depression) and found SAMe to be a safe, effective antidepressant with few side effects and a rapid onset of action. This particular trial is notable as it was the first to report the side effect of mania in a patient who didnt have a previous history.Another is the trial by Rosenbaum (et al 1990). This particular trial is notable for the demonstration of the fact that about 20% of other treatment resistant patients experienced benefit with SAMe.Faya (et al 1990) (II) considered the fact that SAMe is thought to exert its effect through its action in increasing dopamine levels in the synaptic cleft. It is known that dopamine inhibits the production of both Thyroid stimulating hormone (TSH) and Prolactin from the pituitary gland. Faya considered measuring the leve ls of both TSH and Prolactin during treatment with SAMe. His findings constituted something of a surprise insofar as in the men in the trial group had their levels of TSH and Prolactin reduced which is consistent with the hypothesis that SAMe increases the dopamine levels in the brain. Much to everybodys surprise, this effect was not seen in the female group. The authors do not offer any explanation of this fact.For the record, there is another trial (Thomas et al 1987), which obviously considered the same phenomenon and their trial did not show any sex linked difference in the suppression of the Prolactin levelsWith regards to efficacy, a trial by Carney (et al 1986) suggests that the beneficial action of SAMe is restricted to endogenous depression and it does not appear to have any action above placebo on reactive depression. As far as we can ascertain, this is the only trial published that has made this suggestion, although from a first principles basis, one can see the biochemic al rationale for believing that it might well be the case.On a purely empirical grounds, some authors have recommended (on the basis of scant hard evidence), that SAMes action can be maximised by the addition of B12, B6 and folic acid. It is known that SAMe is required to convert these agents into their active form as a coenzyme. (Morrison et al, 1996). The same author also recommends the simultaneous adminstration of Trimethylglycine (TMG) which is necessary for the intracellular conversion of methionine into SAMe by the provision of the necessary methyl- groups. Comment has to be made that again, this appears to be a completely empirical (and logical) suggestion, but we cannot find any hard evidence to substantiate its clinical use.ChemistrySAMe is a basic component of cellular biochemistry. It occurs in every living cell and is second in importance only to ATP in both the number variety and significance of the reactions in which it serves as a cofactor. (Stramentinoli 1987).It is central in the chemistry of the transmethylation reactions. In essence its cellular function is to transfer the active methyl group form carrier molecules to a multitude of other molecules. In general terms, this methylation makes inert molecules biologically active.In addition to the transmethylation reactions it also plays a central role in transsulfuration and aminopropylation reactionsIt is involved in the synthesis of proteins including the nucleic acids, fatty acids, lipids and phospholipids, porphyrins and polysaccharides. In terms of our considerations here, perhaps the most significant reaction type that SAMe is involved in is the generation of the neurotransmitter amines. In this regard it is considered to be the most biologically significant provider of methyl groups within the cell. (Baldessarini 1987). Significantly it is also involved in the pathways to produce a number of other neurologically active compounds such as adrenaline, the neuronutrients acetyl l-carnitine and phosphatidyl choline (Mathews et al 1990)It is also to be found in the metabolic pathways of both serotonin and dopamine. Oral administration has been shown to increase the metabolites of these compounds in the CSF (implying increased turnover). It is thought to exert its antidepressive effect partly through the mechanism of increasing the levels of both dopamine and serotonin as neurotransmitters, but it also appears to have some form of trophic action on some of the neurones in the brain cortex. (Baldessarini 1987)It has been demonstrated that the tissue levels of SAMe tend to diminish with age and blood levels are also found to be low in some cases of clinical depression(Baldessarini 1987)A methyl group (CH3) is a group of three hydrogen atoms bound to one carbon atom. It does not exist in a stable isolated form and is transported between molecules by intermediaries such as SAMe. Methylation is the process by which this group is transferred from the methyl donor molecule to t he recipient molecule.In general terms this process is central to the control of many of the intracellular pathways. Giving a methyl group to an enzyme is often the key to activating it, and thereby beginning a synthesis or degradation process elsewhere in the cell. Equally removing the methyl group will render the enzyme inactive and stop that particular pathway. Similar mechanisms are involved in the expression of genes and therefore the production of proteins within the cell.Some specific methylation reactions include the methylation of phenols which detoxify them and thereby aid in their excretion. (Stramentinoli 1987)In the context of this dissertation, methylation is also central to the metabolic chemistry of serotonin (and therefore also melatonin). The activity of both these compounds is effectively regulated by the presence of a methyl group.SAMe is synthesised from methionine, a naturally occurring amino acid. As the name implies (METH-ionine), it contains a methyl group. By utilising the energy supplied by ATP and in the presence of magnesium, it is converted into SAMe. The process is catalysed by the intervention of the enzyme MAT (methionine adenosyl

Thalamic Glutamate as a Marker of Global Brain Pathology -MS

Thalamic Glutamate as a Marker of Global fountainhead Pathology -MSAuthor contri butionsLP rule conceptualisation of the write up, analysis and interpretation of information, write the disseminated multiple sclerosis for mind content.JR design conceptualisation of the study, data collection, analysis and interpretation of data, drafting the manuscript for intellectual content.IRB analysis and interpretation of data, revising the manuscript for intellectual content.GS analysis and interpretation of dataKZ data collectionRN design conceptualisation of the study, analysis and interpretation of data, drafting the manuscript for intellectual content.LP1DisclosuresLP no disclosures.JR no disclosures.IRV no disclosures.GS no disclosures.KZ no disclosures.RN Bayer, Biogen, Genzyme, Merck Serono, Roche honorarium for speaking, in ar outrankory boards. Biogen, Genzyme, Novartis funds for organising education, staff. Biogen, Novartis Principal investigator.LP2LP3Multipl e sclerosisMultiple sclerosis (MS) is characterised by demyelination and variable degrees of axonal loss and gliosis. plurality with MS (pwMS) present with arresting disturbances, spasticity, fatigue, ataxia, pain and urinary dysfunction1. The most common form of MS is relapsing-remitting and 85% of pwMS initially present with it, with most counterbalancetually progress to a secondary, imperfect tense human body2. Without adequate handling, 25% of pwMS become wheelchair-bound3.Charcot was the first to describe the insurgent demyelinating boldness as a hallmark of MS in the late nineteenth century4. While sporting re knock over lesions (WML) contribute to disability5,6, they argon likely not its only drive. Recent evidence validates the concept that grey count lesions (GML) and shrivel are likely contributors to disability7,8. Furthermore, recent studies have looked at diffuse axonal loss and support the notion that this process drives long-term disability, due to a com bination of focal inflammation and cortical damage driven by meningeal inflammation9-13.Large clinical trials in MS infrequently agree the effect of therapies with head teacher lesion books and atrophy. This is due to the fact that as of today, no alter software exists which is able to consistently calculate WMLs14 and GMLs are grossly underestimated as they are not readily visible on magnetic resonance imaging15,16. Lastly, brain atrophy is hard to quantify, underside only be measured longitudinally and is bailiwick to non-tissue related (pseudo-atrophy) volume loss subsequent to disease modifying treatment17,18. There is an unmet accept for a simple biomarker that can act as a alternate for neural damage in MS for use in observational and interventional studies.NatalizumabNatalizumab (Tysabri) is a disease-modifying treatment abandoned intravenously as a periodic infusion19. In the UK it is licensed as a second-line treatment for severe, rapidly evolving, relapsing-rem itting MS. It is say against the 4 subunit of integrin on lymphocytes and acts as an immune-modulator by inhibiting their migration to the brain20,21. Compared to placebo, it has been shown to reduce revert rate by 68%. Furthermore, it reduced the risk of disability feeler by 42%, defined as a change in EDSS score sustained for 24 weeks21.charismatic resonance spectroscopyMagnetic resonance spectroscopy (MRS) is a non-invasive MRI sequence that allows identification and quantification of in vivo metabolites present in a small, preselected brain region. Proton nuclei (1H) are most usually employ in studies of the human brain due to their abundance and lofty sensitivity. MRS sequences distinguish in the midst of different metabolites by measuring the frequency at which 1H nuclei flip, which is in turn dependent on the molecular free radical carrying the foment content atom22. Measuring these metabolic changes allows researchers to gain an insight into changes at a cellular a nd molecular level in the brain, which cannot be acquired exploitation conventional MRI techniques23.The thalamus is a subcortical hub, with multiple reciprocal connections to both exsanguinous emergence tracts and cortical grey matter24. earlier studies evidenced the fact that it is sensitive to pathology occurring in opposite brain regions25. We speculated that by employ the thalamus as our region of fire (ROI), investigated metabolites would give a measure of global neuronal damage.AimsWe investigated thalamic MRS as a biomarker for global brain neuronal damage in MS by comparing service line metabolite submersions between pwMS and HCs. Metabolites that were found to be statistically probatively different between these two groups at baseline were investigated further. To additionally support utilise MRS imaging as a surrogate for global primordial nervous system pathology, we investigated the correlation between these metabolite concentrations in pwMS and enumerate lesion volume. In order to investigate whether thalamic MRS can be used to monitor treatment response, we measured changes in their concentration following treatment with the disease-modifying drug natalizumab. cosmosParticipants aged 21-65 underwent inclusion criteria screening. For the pwMS group, this included satisfying the McDonald criteria 2010, having super active MS and having been scheduled to initiate natalizumab treatment as part of routine NHS Case. side by side(p) ethics approval and written informed consent from participants, 17 pwMS and 12 HCs were recruited to the study.HCs underwent an MRI baseline scan while pwMS underwent a scan at baseline, and follow-up scans at 10 and 56 weeks after initiation of natalizumab treatment.acquirement of MRS dataAll experiments were carried out in the same Siemens 3T Magnetom Verio with a 32-channel receiver head coilLP4, used to acquire combined MRI and 1H-MRS scans. A magnetisation-prepared rapid gradient-echo sequence (MPRAGE ) was used to set about high-definition T1 weighted scans with the following parameters (repetition m (TR)= 2300secho time (TE)= 3ms everting time (TI)= 900 160 sagittal sections slice thickness 1.0mm in-plane resolution of 1x1mm2 . A hotshot voxel was placed over the leftover thalamus. In order to acquire the single-voxel scans, a Point-RESolved Spectroscopy sequence (PRESS) was used which had variable power and optimized relaxation delays (VAPOR) wet suppression (TR/TE, 2000/30ms) on a single 15-mm slab. This was reoriented to the T1 sequence sections ( portend 2). Four reference transients were used to align the data. The average of 96 transients was used for water suppressed spectra. The volume of evoke was 15x15x15mm, voxel size was 3.4mL. These parameters were in any case used to acquire reference MRS datasets without water suppression. This was through to obtain an internal water reference, which was used to scale metabolite signals. Double everting recovery pulse an d phase sensitive anastrophe recovery sequences were also acquired.Lesion volumesWhite and grey matter lesions were identified on 160-slice T1 scans with co-registered double inversion recovery sequences. Lesions were manually segmented in T1 space using the over-embellished College software ImSeg. The images obtained by this process LP5were used to derive proportions of grey matter, white matter and arrive lesion volumes. T1, double inversion recovery pulse and phase sensitive inversion recovery sequences were used to accord for presence of lesions in the thalamus.Data processingT1 and spectroscopy data were initially obtained from scans in dicom format (dcm). A modified MATLAB (v.2015b) script was used to convert the T1 scans into nifti format (nii), the single voxel spectroscopy scans into rda format (rda) and to generate cover files in rda format.LCModel (v.6.3-1K) was run by using a second modified MATLAB script, in order to obtain spectroscopy data from 0.2-4.0 ppm. The s oftware is a user-independent fitting routine that kit and caboodle by superimposing spectra obtained in vivo with high-resolution model spectra. It is an accurate and reliable system to quantify MRS data with short echo times (ET30ms)28,29.Partial volume subjects to explain different concentrations of water in the grey matter (GM), white matter (WM) and cerebrospinal fluid (CSF) were conducted by converting T1 sequences from dicom to nifti format, and segmenting the obtained images using MATLABs SPM8 toolbox. This allowed grading metabolite concentrations obtained from PRESS sequence with water-suppression, to the waters internal reference signal from the uninhibited water PRESS-sequence.The segmentation was used to calculate voxel proportions of GM, WM and CSF, which are in turn needed to obtain the water concentration (WCONC) value from the unsuppressed water reference signal used to estimate absolute concentrations of metabolites. Total WCONC value for each voxel were compu ted in accordance with Section 10.2.2.3 of the LCModel manual29.Eddy-current correction was performed by using LCModel. Relaxation effects were not corrected for, and therefore account metabolite concentrations go out differ from actual ones by an unknown factor. The latter is likely to be negligible, as all describe concentrations will deviate from actual concentrations by this same, unknown factor. As per LCModels manual, metabolite concentrations were multiplied by a factor of 1.04, which amounts to the proper(postnominal) gravity of brain tissue29, and were reported in mmol/L (mM).Data expulsionA heat map (Figure 4, right side) was created in order to check for voxel placement by using FSL view v.3.2.0. T1 sequences and mask files were reoriented to match the Montreal neurologic Institute standard template, followed by brain extraction from the surrounding tissue. T1 sequences and mask files were registered to standard space using the Montreal Neurological Institute templa te, which consists of 152 averaged brain T1 scans of 2mm resolution. The heat map is a depiction of each voxel mask overlaid onto the che2better template for T1 sequences taken from the mricron software.LP6 No MRS spectra were removed from the analysis owing to minimal inter-scan variability. Spectra generated by LCModel were checkered for overall data quality in accordance with the softwares instruction manual29. 2 baseline HC and 2 pwMS spectra were excluded from data analysis (Table 1).For a metabolite to be investigated, it had to be relevant to MS pathology as evidenced by previous studies, as well as to demonstrate sufficient data quality, measured by having Cramr -Rao get bounds ratio of 75% of soulfulness scans. Five metabolites were investigated choline-containing compounds (Cho), glutamate (Glu), myo-inositol (Ins), total creatine (tCr) and total n-acetylaspartate (tNAA) (Table 1). In a devoted subjects scan, metabolite concentrations with a Cramr-Rao lower bounds (CR LB) value of 15% were excluded from data analysis, as per LCModels manual of instructions. Concentrations exceeding 2 standard difference of opinions (2SD) out with the group mean were also excluded.QCa for entire spectraQC for individual metabolites Participant group in advance spectra QC(n) aft(prenominal) spectra QC(n)Metabolites (marker of)6 Participant groupBefore metabolite QC(n)After 1st QCf(n)After 2nd QCg(n)HCsb1210Cho1(membrane turnover)HCs1099pwMS BLc1715pwMS BL151212pwMS 10wd1616pwMS 10w161616pwMS 56we1616pwMS 56w161515Glu2(metabolism and neurotransmitter activity)HCs1066pwMS BL1598pwMS 10w161414pwMS 56w161514Ins3(glial marker)HCs1077pwMS BL151414pwMS 10w161514pwMS 56w161515tCr4(metabolic activity)HCs101010pwMS BL151514pwMS 10w161615pwMS 56w161616tNAA5(neuronal loss, mitochondrial activity)HCs10109pwMS BL151514pwMS 10w161616pwMS 56w161615statistical analysisPrism GraphPad (v.7) and IBM SPSS Statistics 24 software were used to conduct statistical analysis. Participant de mographics results are reported as mean and standard deviation (SD). Metabolite concentrations are reported as mean, standard error of measurement (SEM) and 95% confidence intervals. Parametric tests were used after testing for normal scattering of the data. Unpaired t-tests were used to liken metabolites between pwMS and HCs cross-sectionally. Pearsons coefficient was used to correlate between metabolite concentrations and bilateral lesion volumes. A linear mixed model was used to quantify longitudinal changes in metabolite concentrations in pwMS.MRS data were obtained from 17 pwMS (mean age (SD) was 41.6 (10.6), range 21-58 years) and 12 HCs (mean age (SD) was 41.9 (8.3), range 29-61 years). Mean time since diagnosis in years was 12.1 (10.6) and mean Expanded Disability Status Scale (EDSS) was 4.1 (1.1).People with MS, n17Age, mean (SD)41.6 (10.6)Sex, n (%)M6 (35)F11 (65)Years since diagnosis, mean (SD)12.1 (10.6)EDSS score, mean (SD)4.1 (1.1)Healthy checkers, n12Age, mean (SD) 41.9 (8.3)Sex, n (%)M9 (75)F3 (25) visit concentrations of glutamate are found at baseline in the thalami of people with highly active MSA statistically authoritative difference in the concentration of glutamate was found between the two groups (7.670.3456 in HCs and 6.550.232 in pwMS, p=0.016). No significant difference was found between the two groups using other metabolites.MetaboliteHealthy controls (n=10) People with MS (n=15) 95% CICho1. 690.0826,n=91.750.25, n=12-0.232 0.216Glu* 7.670.346, n=66.550.232, n=8*-2.00 0.253Ins3.980.250, n=74.450.281, n=14-0.452 1.380tCr340.134, n=105.420.150, n=14-0.350 0.510tNAA8.600.134, n=98.460.178, n=14-0.656 0.375 baseline thalamic glutamate concentrations in pwMS correlate negatively with total lesion volumesBaseline glutamate concentrations in pwMS negatively correlated with T1 scan total lesion volumes (n=8 r=-0.80, p=0.017 Figure 6). No other thalamic metabolite correlated with lesion volumes. Lesion volumes in HCs (n=6) were assum ed to be postal code and are depicted in Figure 6, but this parameter was excluded from statistical analyses. No lesions were found in the thalami of pwMS in this study.Glutamate concentration correlated even more strongly with left hemisphere lesion volumes (p=0.0091), an expected finding given that the left thalamus was used as the studys ROI. The correlation was least significant when using right hemisphere lesion volumes (p=0.030). These results are reported in Table 3.Sampled lesion load locationr, correlation coefficientp-value Left hemisphere-0.840.0091Right hemisphere-0.750.030 twain hemispheres/Total-0.800.016Thalamic glutamate concentrations increment following natalizumab treatmentGlutamate concentrations measured in the thalami of pwMS change magnitude significantly (p=LP7) between the 10 and 56 weeks (n=12 pairs of data-points) follow-up scans. At 56 weeks, no significant difference between the pwMS and HC groups was recorded, suggesting that glutamate levels had nor malisedLP8. No significant difference in glutamate concentration was recorded between baseline and 10 weeks follow-up scans (n=7 pairs of data-points) and between baseline and 56 weeks follow-up (n=7 pairs of data-points).LP9This observational study used proton magnetic resonance spectroscopy (1H-MRS) to compare metabolite concentrations in 17 pwMS and 12 HCs. Study findings indicate a lower baseline concentration of glutamate in the thalami of pwMS compared to HCs. In pwMS this correlated negatively with total baseline brain lesion volume, which supports our initial hypothesis that thalamic MRS specifically measuring glutamate can be used as a surrogate for global primaeval nervous system pathology. An increase in glutamate concentrations was recorded following natalizumab treatment between 10 and 56 weeks of follow-up. To our groups knowledge, this is the first 1H-MRS study to identify baseline cross-sectional differences in thalamic glutamate, correlate glutamate concentrations with total lesion volumes, and report longitudinal changes in thalamic glutamate following natalizumab treatment.Thalamic glutamate is a potency surrogate for total brain neuronal damage in highly active MSGlutamate, the chief telephone exchange nervous system excitatory neurotransmitter is mainly synthesized from glutamine31,32. In addition to its neurotransmitter role, glutamate concentration is closely linked to the Krebs cycle, which reflects the cells metabolic activity. Previous proton MRS studies in MS reported higher levels of glutamate in lesioned white matter of pwMS compared to HCs33,34. One of these studies also reported lower levels of glutamate in lesioned grey matter regions34. The limitation of using white or grey matter lesions as ROIs is the high heterogeneity of these brain regions. With regards to WMLs, their definition includes- among others- active, inactive and remyelinating lesions. As for grey matter, this can be bear upon by exposure to cytokines from me ningeal follicle-like structures or, similarly to WMLs, demyelination13,35,36. Current MRS imaging is unavailing to discriminate between these different pathologies. Therefore, metabolite concentrations obtained from these ROIs are likely to reflect the aforesaid(prenominal) local pathological changes, rather than global MS pathology. In contrast, the potential advantage of thalamic MRS is that the thalamus is rarely affected by local inflammation in MS37,38. Given that it is a subcortical hub highly connected with numerous other brain areas, this study hypothesised that the thalamus could be used as a biomarker of total brain neuronal damage in highly active MS. dickens results in our study support this hypothesis the decreased concentration of glutamate in pwMS and the negative correlation between glutamate and total brain lesion volume. Lesion volumes in MS have been found to correlate with axonal loss39 and disability40. Moreover, glutamate is mainly found in synaptic vesicles , therefore the decreased thalamic glutamate recorded in pwMS in this study could represent neuronal degeneration and synapse loss.Thalamic glutamate increases following natalizumab treatmentBetween 10 and 56 weeks of natalizumab treatment our group recorded a significant increase (p=,) in the concentration of thalamic glutamate in pwMS. At the end of the follow-up period, glutamate levels normalised, with no significant difference being recorded between pwMS and HC groups. No significant differences in glutamate concentration were found between baseline and 10 (n=x pairs?) and baseline and 56 weeks (n=x pairs?)LP10 follow-up scans. It can be hypothesised that the exceptional prove size of pairs of data-points between baseline and 56 weeks follow-up glutamate prevented us from recording an existing statistically significant difference. With regards to changes in glutamate between baseline and 10 weeks, there could be a significant change in glutamate concentration within this time frame, which was not picked up due to our limited sample size. It also cannot be excluded that thalamic MRS may take longer to respond to treatment.Previous published literature has shown lower glutamate concentrations in lesioned white matter of pwMS at baseline, which increased following treatment with natalizumab41. This effect can be attributed to the anti-inflammatory proprieties of natalizumab. By preventing production of nitrogen oxide and reactive oxygen species by macrophages, the drug could reduce axonal damage otherwise piddled by these compounds42,43.Study limitationsThe algorithmic program used my SPM8 is incapable of accurately differentiating between the brighter grey and surrounding white matter, as the image intensity level in the thalamus is very close to the intensity of white matter. Therefore the software records a higher white matter proportion in the thalamus than the true one. It should be however noted that this inaccuracy in measuring white/grey matter r atio should not cause any systematic error that would affect overall results.The studys HCs were adequately age-matched but poorly gender-matched to pwMS. Previous studies however reported no significant differences in any of the metabolite concentrations in the brain between different genders44. Therefore, no correction for a gender effect was made.The HC group only had a baseline scan, with no longitudinal data recorded. A useful longitudinal control group may be untreated pwMS. The absence of such a control group is currently however a common limitation, as people with highly active MS are nearly incessantly on treatment. Having no information on the natural history of thalamic MRS in pwMS, it is difficult to interpret the significance of longitudinal changes in glutamate seen in this study.Lastly, albeit the thalamus is rarely affected by inflammatory activity in pwMS, the presence of inflammatory lesions has been previously described45. Such lesions are a confounding factor a s they directly influence measured metabolite concentrations. However, based on T1, double inversion recovery pulse and phase sensitive inversion recovery sequences, no thalamic lesions were observed in our study.Future workStudies with larger sample sizes are needed to confirm our baseline findings, as well as to confidently interpret longitudinal changes in glutamate concentrations following natalizumab treatment. The presence of a pwMS untreated control group is not justifiable on ethical and healthy grounds, however fu