Groups and High-Performance Teams

Abstract Today’s leaders face many challenges in the creation of a high-performing team. Effective leaders are able to assemble a high-performance team with good hierarchical balance, measurable and attainable goals, and appropriate communication expectations across the team. They promptly address conflict resolutions and break down all physical barriers in managing multi-city offices and dispersed employees. By paying close attention to team demographics and diversity, good leaders will establish a solid group foundation which will result in a high-performance team.Groups and High-Performance Teams There are many factors that affect a team’s behavior and overall performance. Group demographics and diversity can ultimately play a key role in the success or failure of any team. This paper will identify some of the challenges that today’s leaders face in turning a group into a high-performance team, and the impact of demographic characteristics and cultural diversi ty on group behavior. Groups vs. Teams As defined by Schermerhorn (2005), â€Å"A group is a collection of two or more people who work with one another regularly to achieve common goals.An effective group is one that achieves high levels of task performance, member satisfaction, and team viability. † Teams on the other hand, are usually time-limited groups that get together to achieve a common purpose. â€Å"An essential criterion of a true team is that the members feel ‘collectively accountable’ for what they accomplish. † (Schermerhorn, 2005). The manager or team leader must remember the importance of the team members’ ability to associate themselves with a group identity and begin to form an attachment to their teammates. The fact is that it takes a lot more work to build a well-functioning team than simply assigning members to the same group and then expecting them to do a great job. † (Shcermerhorn, 2005). Team Identity Setting a teamâ₠¬â„¢s identity is one of the first steps a manager must take in forming a high-performing team. As we often witness in the sports world, a team’s identity can help to rally team members and build camaraderie amongst its members. The same approach holds true in a business setting. Computer Weekly (2004) reports, â€Å"The project start process can also be used to build team identity and build psychological attachment between members. (p. 24). This psychological attachment will serve as the foundation upon which the team is built and will affect the team’s overall performance. According to Turk (2005), â€Å"As the project manager you need to build a staff that can get the job done. You need the right mix of expertise, creativity, flexibility, enthusiasm, and experience. † ( p. 30). These key attributes will work to motivate other team members and assist the manager in establishing the appropriate balance to the team. Team Diversity When forming effective teams, managers must consider team synergy an important goal, and diversity plays a major role.Managers should strive to create the appropriate balance between workers and their personality types. As Martinette (2005) points out, â€Å"Work groups and teams that have too many people of one type or another soon find themselves out of balance. † (p. 117). â€Å"For good problem solving and decision making, you need a diversity of personality types. † (Hill, 2005, p. 37). Striking the proper team balance is important and balance does not mean people with a background and disposition just like the boss. Many types of diversity are to be expected on any team, and can be the source of many differences of opinion.Age, gender, ethnicity, and personality differences can affect the team’s cohesiveness, or non-cohesiveness as may be. Obviously, with a diverse group the possibilities of conflict increase, but so do the possibilities of a greater outcome. Hill (2005) gives us an ex ample, â€Å"Meetings are more raucous and consensus is harder to achieve. But these arguments often spark new ideas. As a result, the company is constantly spawning and sculpting new innovations in a way the old team never did. † (p. 38). Differences in world view can create dynamic conversations and results, if the team can learn how to effectively deal with conflict.According to D Andrea-O Brien and Buono (1996), â€Å"True team learning is the ability of members to†¦ build on their knowledge so that their collective knowledge enables them to continually improve team†¦ performance as well as to discover, develop and implement completely new ways of doing business (p. 1). Demographics Managing remote employees is a growing challenge for many of today’s leaders. It is not just about managing employees at satellite offices; it is also managing telecommuters who work a certain number of days from their home offices.A manager needs to understand the complexiti es of managing a virtual team and communicating across the boundaries of time zones, organizations and cultures. Good communication practices as well as building personal relationships are both key to working with remote employees. As Pauleen (2003) states, â€Å"Effective communications is a key to successful virtual teams, and one of the keys to effective communications is how well team members are able to build and maintain their personal relationships. † (p. 229).Video conferencing works well and provides a company’s employees with a visual link that serves to backfill for the lack of face-to-face communications that employees would have if they were collocated. Trust and Motivation An important goal for managers, in addressing and monitoring a team’s behavior, is to develop the trust of his or her team members. Employees that trust one another will often be motivated to go the extra mile in meeting and exceeding team objectives. Team motivation is extremely important because it makes the team more effective.Stephen Covey (1989) states: â€Å"Unclear expectations in the area of goals also undermine communication and trust. † (p. 194). If goals seem unachievable, it could affect the teams buy-in to the whole process. Giving, receiving and being responsive to feedback should be a fundamental part of the team process. Conflict According to DeJanasz, Dewd and Schneider (2001), â€Å"Conflict is any situation in which there are incompatible goals, cognitions, or emotions within or between individuals or groups that lead to opposition or antagonistic interaction. † (p. 243).Conflict among team members is inevitable and desirable, because â€Å"conflict in itself is not the problem. It is, rather, our reactions to it that determine the impact, and causes us to characterize it as a negative experience. † (Porter, 2005, p. 1). It should be anticipated that the team will disagree, and therefore, conflict should be considered a part of the process. â€Å"In fact, if we define conflicts as simply differences of opinion, this is exactly what we want to happen. In bringing together a diverse group of experts, we expect and want these differences to surface because, in the end, we expect a better outcome or result. (The Team, p. 171). If everyone agreed, there would be no reason to team up to resolve a situation, or to come up with new ideas. Teams are developed for a specific purpose, and diverse opinions, ideas, and perspectives will make the team most effective. Conclusion Team diversity and demographics play a key role in determining the success or failure of any team. An appropriate understanding and acceptance of a diverse group will benefit the organization through innovative and diverse ideas. â€Å"Of course, that doesn’t mean you should go out of your way to hire people you don’t like.While a certain measure of conflict is healthy, too much conflict can be destructive. † (Hil l, 2005, p. 39). Paying close attention to team identity, trust, diversity, motivation and conflict resolution will go a long way in paving the road for a successful team outcome. Employees will appreciate that their leadership cares about these issues and will reward the team with their best efforts in meeting goals, which results in a high-performance team. References Computer Weekly. (2004, June). Plan your web project milestones. Computer Weekly. 4-54. Retrieved October 8, 2005 from Business Source Premier database. Covey, Stephen R. (1989). The Seven Habits of Highly Effective People: Powerful Lessons in Personal Change. New York: Fireside. D Andrea-O Brien, Charlene & Buono, Anthony F. (1999, Summer). Building effective learning teams: Lessons from the field. S. A. M. Advanced Management Journal, 61(3), 1-6. Retrieved September 23, 2005, from ProQuest database. DeJanasz, Dewd & Schneider. (2001). Conflict: Sources and solutions. Interpersonal Skills in Organizations. Universit y of Phoenix Custom Edition e-text]. McGraw-Hill Companies. Retrieved October 3, 2005, from University of Phoenix, rEsource, GEN 300 – Skill for Professional Development Course Web site: https://ecampus. phoenix. edu/secure/resource/resource. asp. Hill, Dee. (2005, November). Dealing with diversity. Inc. , 27(11), 37-40. Retrieved January 13, 2006, from Academic Search Premier Database. Martinette, Jr. ,C. V. (2005, April). Leadership and Balance. Fire Engineering, 158, 117-126. Retrieved October 8, 2005 from Academic Search Premier database.Pauleen, David J. (2003, Winter). An Inductively Derived Model of Leader-Initiated Relationship Building with Virtual Team Members. Journal of Management Information Systems, 20, 227-256. Retrieved October 7, 2005 from Business Source Premier database. Porter, Sheila, J. D. Managing Conflict in Learning Teams. [University of Phoenix Custom Edition e-text]. Retrieved September 28, 2005, from University of Phoenix, rEsource, GEN 300  œ Skills for Professional Development Course Web site: https://ecampus. phoenix. edu/secure/resource/resource. asp.Schermerhorn, Jr. J. R. , Hunt, J. G. , and Osborn, R. N. (2005). Organizational Behavior (9th ed. ) Wiley. Hoboken, NJ. The Team Working Together. Chapter 12. [University of Phoenix Custom Edition e-text]. Retrieved September 26, 2005, from University of Phoenix, rEsource, GEN 300 – Skills for Professional Development Course Web site: https://ecampus. phoenix. edu/secure/resource/resource. asp. Turk, Wayne. (2005, May/June). Quality Management – A Primer. Defense & AT-L, 34, 30-33. Retrieved October 7, 2005 from Business Source Premier database.

Behavioral Management Theory Essay

As management research continued in the 20th century, questions began to come up regarding the interactions and motivations of the individual within organizations. Management principles developed during the classical period were simply not useful in dealing with many management situations and could not explain the behaviour of individual employees. In short, classical theory ignored employee motivation and behaviour. As a result, the behavioural school was a natural outgrowth of this revolutionary management experiment. Discuss – how behaviour management has changed over the years in the modern classroom we know today ? The behavioural management theory is often called the human relations movement because it addresses the human dimension of work. Behavioural theorists believed that a better understanding of human behaviour at work, such as motivation, conflict, expectations, and group dynamics, improved productivity. Discuss – How does a better understanding of human behaviour enhance our own teching The theorists who contributed to this school viewed employees as individuals, resources, and assets to be developed and worked with — not as machines, as in the past. Several individuals and experiments contributed to this theory. Elton Mayo’s contributions came as part of the Hawthorne studies, a series of experiments that rigorously applied classical management theory only to reveal its shortcomings. The Hawthorne experiments consisted of two studies conducted at the Hawthorne Works of the Western Electric Company in Chicago from 1924 to 1932. The first study was conducted by a group of engineers seeking to determine the relationship of lighting levels to worker productivity. Surprisingly enough, they discovered that worker productivity increased as the lighting levels decreased — that is, until the employees were unable to see what they were doing, after which performance naturally declined. Although the above experiments at the Western Electric Company seem pretty basic – it’s interesting to note how productivity increased when workers concerns were addressed and considered – do we think that the increased productivity is linked to employees feelings of value A few years later, a second group of experiments began. Harvard researchers Mayo and F. J. Roethlisberger supervised a group of five women in a bank wiring room. They gave the women special privileges, such as the right to leave their workstations without permission, take rest periods, enjoy free lunches, and have variations in pay levels and workdays. This experiment also resulted in significantly increased rates of productivity. Again the above experiment appears to give employees control over their working conditions and can this flexibility within the workplace contribute to the individuals feelings of self worth within their organisation – or can the lack of routines/boundaries allow a slip shod working pattern In this case, Mayo and Roethlisberger concluded that the increase in productivity resulted from the supervisory arrangement rather than the changes in lighting or other associated worker benefits. Because the experimenters became the primary supervisors of the employees, the intense interest they displayed for the workers was the basis for the increased motivation and resulting productivity. Essentially, the experimenters became a part of the study and influenced its outcome. This is the origin of the term Hawthorne effect, which describes the special attention researchers give to a study’s subjects and the impact that attention has on the study’s findings. The general conclusion from the Hawthorne studies was that human relations and the social needs of workers are crucial aspects of business management. This principle of human motivation helped revolutionize theories and practices of management. Abraham Maslow, a practicing psychologist, developed one of the most widely recognized need theories, a theory of motivation based upon a consideration of human needs. His theory of human needs had three assumptions: †¢Human needs are never completely satisfied. †¢Human behaviour is purposeful and is motivated by the need for satisfaction. †¢Needs can be classified according to a hierarchical structure of importance, from the lowest to highest. My interpretation of the experiments and the correlation to Maslow’s theory below demonstrates to me the importance of setting ground rules in the first instance is paramount to ensuring workers or learners in our case – have some autonomy over their patterns of working increasing motivation and individual feelings of self esteem over their learning journey! Maslow broke down the needs hierarchy into five specific areas: †¢Physiological needs. Maslow grouped all physical needs necessary for maintaining basic human well-being, such as food and drink, into this category. After the need is satisfied, however, it is no longer is a motivator. †¢Safety needs. These needs include the need for basic security, stability, protection, and freedom from fear. A normal state exists for an individual to have all these needs generally satisfied. Otherwise, they become primary motivators. †¢Belonging and love needs. After the physical and safety needs are satisfied and are no longer motivators, the need for belonging and love emerges as a primary motivator. The individual strives to establish meaningful relationships with significant others. †¢Esteem needs. An individual must develop self-confidence and wants to achieve status, reputation, fame, and glory. †¢Self-actualization needs. Assuming that all the previous needs in the hierarchy are satisfied, an individual feels a need to find himself. Maslow’s hierarchy of needs theory helped managers visualize employee motivation. Douglas McGregor was heavily influenced by both the Hawthorne studies and Maslow. He believed that two basic kinds of managers exist. One type, the Theory X manager, has a negative view of employees and assumes that they are lazy, untrustworthy, and incapable of assuming responsibility. On the other hand, the Theory Y manager assumes that employees are not only trustworthy and capable of assuming responsibility, but also have high levels of motivation.

The Advent of the Renaissance

To what extent is the term â€Å"Renaissance† a valid concept for a distinct period in early modern European history? Prior to the 14th century, the Middle Ages revolved around the basic understanding of the Bible. Middle to lower class citizens relied heavily on the teachings of the priest's and blindly followed their ways of living. The church discouraged any new concepts and believed that life on Earth was simply a preparation for the after life.The Renaissance, ranging from the 14th to 16th entries, became a distinct period in European history due to the increase in trade, influence of art and the artist, and the growing phenomenon of individual thinking, as this will lead to future exploration and economic advances. Italy, the epicenter of Renaissance culture, was able to advance their society through a growth in economic stability. As ships and trade routes began to advance technologically, the Italian merchant class also grew.Italian merchants and sailors would import g oods from all over Europe, such as wool from England, and ship them o other countries. The risks of such endeavors were high, but the end profit was even higher. This new industry not only stabilized the Italian economy, but it eventually led to the development of the Urban Nobility class, who strongly contributed to the Renaissance efforts. During the Renaissance, the influence of art and the artist grew extensively. Artists in the Middle Ages worked strictly on religious pieces for the church and many struggled to make a reasonable living.Art during the Renaissance was in high demand. Every rich and powerful family used works of art as a way to flaunt their wealth and demonstrate their lavish lifestyle. The technique of dark and light was added to show depth and dimension. Artists also began to use realism, painting more realistic faces and bodies, as this was a newly accepted style. Some of the highly influential Renaissance artists include Michelangelo, Leonardo dad Vinci, Rapha el, and Ghetto. Their works were not only revolutionary for their time, but they continue to be inspirations for the modern day artist.Through the invention of the printing press, revolutionary thinkers were able to communicate their theories to the mass population, an opportunity that was never accessible prior to the Renaissance. Three main proprietary concepts were developed in this time. The ideas of humanism, individualism, and secularism dominated the Renaissance culture like never before. Humanists emerged with a newfound interest in the classics. They studied these works in order to discover more about human nature.Individualists prioritize the potential of the human being. They believed that everyone should have to opportunity to be the best they can possibly be. Secularism was the basic concern with the material world, as opposed to the spiritual world. These ideas strongly opposed the teachings of the church, yet they continued to spread rapidly and strongly. Coming out o f a banal period in western culture, the Renaissance brought on countless revolutionary thinkers that worked to open the eyes of their peers and make an impact on society.The Renaissance was an explosion of revolutionary ideas that spread all across Europe. For the first time in centuries, artists, merchants, writers, and philosophers alike were able to express themselves in an amazing way. Many of the greatest minds that we often look back to for inspiration originated from the Renaissance era. Their ideas made a lasting impact on culture, then and now. The Renaissance would not have been such a distinct period if not for the combined efforts of every possible industry and art form.

Childrens Cognitive Development Assignment Example | Topics and Well Written Essays - 500 words

Childrens Cognitive Development - Assignment Example Both teachers report at motivation is easy to achieve in 2nd and 4th grade because children still seek to please authority figures at this stage in their development. Rewards for good behavior, such as extra recess time are no longer possible because so much time is devoted to standardized testing. These teachers have adapted by offering students more choices about how and what they learn within the classroom. Differentiated instruction is a key to motivation and classroom management in elementary school. Both teachers agree that there is a difference between what they feel parents should do for their child’s education and what they actually see happening. Both teachers feel a stable home with good nutrition, boundaries concerning bed times and video games, and exposure to books and literature are all helpful. A home with scheduled study times was also identified as being a plus. Bothe teachers agree in stating that less than half of their children now have this sort of a home. Even the affluent, educated kids seem overscheduled and parents appear overindulgent when it comes to permitting TV watching and playing into the late hours of the evening. Kids seem tired and restless according to the 4th grade teacher. I interviewed the principal of a middle school for the next set of questions. She related that Gifted children have their needs addressed in two ways. One of the methods employed is to write specific skills or activities the classroom teacher must develop and do as a part of fulfilling the GIEP. This ensures that students are challenged within the regular classroom setting. She pointed out that inclusion is an important concept for Gifted students as well as students with learning disabilities. The second method employed is through the district Gifted Coordinator. This individual meets one day out of six with the gifted students in the

Management accounting and control Essay Example | Topics and Well Written Essays - 2500 words

Management accounting and control - Essay Example It acts as a plan developed by experts from within the organization or belonging to external agencies, private or governmental. These professionals make forecasts based on assumptions related to the prices of goods produced, costs of production, wages of labour, level of demand in the market and several other variables. These assumptions are then distributed in the form of a budget to the various departments from the head office. The employees in these departments then infer the status of their respective departments and figure out the ways of action depending on their level of knowledge about the market. Therefore in effect the budget comes true only to the extent up to which the specific departments make accurate assumptions regarding their own operations and also the condition of the market. The moral of this entire process lies in the advice lent out to the different departments that they must try and act in a little more efficient way and that they should be selling more amounts of the products in the coming years (Wallander, 1999). This context is good enough to prove redundancy of the intricate system of budgeting in organizations. The management can also do it without taking refuge under complicated assumptions but rather check at regular intervals that the departments are following the advice. In this paper we shall look into the issue that the process of budgeting is no longer a relevant system for running an organization successfully and that it has been termed by a most well known Swedish author as â€Å"an unnecessary evil† (Chapman, Hopwood and Shields, 2009). Considerable amount of debate has arisen regarding the necessity of budgets in business organizations. The process of preparing an annual budget embodies a lengthy process incurring huge expenses. Thus as Hope and Fraser calls it, the system of budgeting is quite cumbersome and is

The Impact of Transportation on the Environment Essay

The Impact of Transportation on the Environment - Essay Example From this paper it is clear that  the impact of the transportation industry on the environment can be classified into three categories such as direct impact, indirect impact and cumulative impact. Direct impact deals with immediate consequences of transportation activities on the environment where the cause and effect relationship is clearly specified or explained. Indirect impact explains the secondary   impact or effect of the transportation activities on the environment.This essay discusses that  the consequences of the indirect impact are higher as compared to the consequences of direct impact of transportation on the environment but the relationship between the direct and the indirect impact of the transportation on the environment is difficult to establish. Cumulative impact can be considered as the multiplicative, additive or synergic consequences of transportation activities on the environment. The cumulative impacts take into consideration the varied or different impac ts of the transportation on the ecosystem which are generally unpredictable in nature.   The transportation industry selected for discussion in this paper is trucking industry.   The trucking industry is often subsidized by public sector especially through the maintenance and construction of road infrastructure which is generally free of access. In developed countries the environmental regulations have been imposed by the government to reduce the emission of individual vehicles.

How important is it for China to train a substantial number of Essay

How important is it for China to train a substantial number of accountants in the near future - Essay Example The need to train more would continue because China would be relentless in pursuing economic reforms. The pursuit would attract more foreign investments and encourage more Chinese companies to expand overseas. China President Hu Jintao indicated that there will be no turnabout from the economic reforms and opening - up in the past three decades that made China achieve "the historic transformation from a highly-centralized planned economy to a robust socialist market economy and from a closed and semi-closed society to one that fully embraces the world." President Jintao spoke before the 13th economic leaders meeting of the Asia-Pacific Economic Cooperation in Peru in November 2008. "We are keenly aware that China remains the largest developing country in the world," Jintao said, "and the difficulties and problems we face in the course of development are rarely seen elsewhere in terms of both their scale and complexity." (Xinhua, http://english.peopledaily.com.cn/90001/90776/90785/6538647.htm, accessed December 6, 2008) Rapid economic growth would require companies to hire external auditors, financial consultants, tax experts and their own internal accounting staff. Training more accountancy manpower would be part of the financial infrastructures of corporations, said Cui Jianmin, president of the Chinese Institute of Certified Public Accountants (2004). "As China adopts a more pro-active approach to attracting foreign investment, there will be a need for auditing, asset valuation and financial advisory services. As China adopts international practice in the field of banking, securities and insurance, it will lead to an increase in demand for accounting firms with a competitive edge. And as China's capital market and bank loans market for small- and medium-sized enterprises also develops, there will be a need for more auditing, capital verification, asset valuation and consulting services. " (Cui Jianmin, interviewed, April - June 2004, Australian CPA Network, , http://www.cpaaustralia.com.au/cps/rde/xbcr/SID-3F57FECB-A56CA432/cpa/network_cui.pdf, p. 18 - 19, accessed December 6, 2008) The importance of training more accountants is illustrated in China's stock exchanges. Listed companies need accountants who can render credible financial information and disclosures for the use of investors and not for taxation authorities. Until 2007 when government mandated new accounting rules, accountants were influenced by tax regulations designed to make sure corporate taxpayers would not minimize their tax payables. Consequently, according to the International Finance Corp. in a study, incomes were overstated and allowable deductions were disallowed. "This explains the apparent paradox that despite a rigid accounting system, enterprises have strong incentives to use loopholes in the system to meet profit targets," the IFC reported. (IFC, Role of Stock Markets and Information Disclosure in the Corporate Governance of Listed Companies http://www.ifc.org/ifcext/publications.nsf/AttachmentsByTitle/CorpGovernanceinChinaChp5/$FILE/CGinChina_Chp.5.pdf, p. 14, accessed December 6, 20 08) A broker, interviewed by the Financial Times, complained about the low quality of financial information available to investors. "The level of disclosure is not good," said

Critically examine the role that technology can play in the Essay

Critically examine the role that technology can play in the recruitment and selection proces - Essay Example Many human resource practitioners spend a huge amount of time in handling activities related to recruitment and selection of new employees (Florea & Badea 2013). Most of these activities might include one-off recruitment episodes to grand recruitment campaigns launched to recruit and select replacement staff, trainees, staff with skills, graduates and many more (Martin,Whiting & Jackson 2010). Due to this engagement, the human resource managers find it easy or difficult to meet the required standards of an organization. It is because of this tedious work most human resource mangers undergo that has le d to the mass adoption of technology in the whole process of recruitment and selection. According to available literature studies, almost 98% of all organizations in the world have incorporated the use of technology and internet in carrying out the process of recruiting and selecting new employees into the workforce. With the ever increased advancement in technology, it is arguably true that recruitment is the most technologically influenced sector in any organizational setting. According to Aarhus (n.d), e-recruiting has taken centre stage and has fundamentally influenced the corporate recruiting process starting from the batch mode to the continuous mode, leading to a major change in the way the business is done. Ensher, Nielson and Vallone (2002) contend that most companies have adopted the most elaborative and creative methods to procure the services of the most qualified talents from the ever sinking pool of talent. More specifically, the human resource managers are currently using technology and the internet to enhance the process of recruitment and selection. As reported by the CMA, the use of technology and internet in the recruitment and selection increased from just 29% in 1998 to 88% by the year 2001. Ensher et al. (2002) further points out that the use of technology in the Human reso urce management is witnessed in three broad

How to be succesful with online dating Essay Example | Topics and Well Written Essays - 250 words

How to be succesful with online dating - Essay Example The platforms promote peace and understanding across the globe and enables people to find appropriate soul mates. Nonetheless, dating online sometimes frustrates, annoys and heart brakes potential soul mates. The following guidelines shall help improve anyone’s chances of attracting the special person in life. The first step to ensuring success in online dating is an excellent profile picture. Photos attract and market your image to potential mates. They also distinguish individuals from a pool of people searching for partners online (Strauss 1). Hence, invest in a catchy picture and entice many people then start your vetting process. Second, write an appealing information about yourself. Express your likings, interests and define the type of people you would like to date. Third, communicate with people who exhibit similar interests with yours in terms of age, region, and sexual orientation. Online sites contain different people, and some may be malicious. Therefore, take your time and use instincts to judge from the conversations. Fourth, do not rush or hurry things up and meeting people. Dating is a gradual process and always gains trust and meet potential matches in open places. Fifth, seek the services of a dating coach to help improve your online image and

Design Human interfaces for Operating Systems Research Paper

Design Human interfaces for Operating Systems - Research Paper Example Since then super computers have been transformed several times, first to desktop computers, then laptops and now cutting edge tabs and pads, thus becoming widely used and an inevitable part of the human life. However, the science behind computers is quite enthralling and it makes a person wonder how exactly a machine is able to perform such complex tasks within mere seconds. First of all it is quite clear that computers do not understand human language, or High Level Language (HLL), and at the same time, humans do not understand machine language, which is basically in binary codes. Thus, it becomes clear that between the computer and the person or user, there needs to be a translator that can translate the languages in order for both parties to understand the other. In case of computer, this is done by the program translators, which consists of assembler, compiler and interpreter. Thus, it becomes clear that by converting high level language and program language into machine language, the computers can understand what the user tries to communicate, and similarly, by converting machine language into program language or high level language, the user can make sense of what the computer is c ommunicating. However, there still needs to be a platform where these communications can take place. This is where the operating systems of computers come into play, as it is them that provide a basic platform for the user to interact with the computer system through interface or human interface. Therefore, it becomes clear that the design of operating systems and human interfaces need to be done in a way that it enable maximum utilization to the user. An operating system is a software program, which facilitates the management of â€Å"hardware and software resources of a computer† and performs tasks including â€Å"controlling and allocating memory,

Working With HIV and AIDS Essay Example | Topics and Well Written Essays - 500 words

Working With HIV and AIDS - Essay Example Since it was discovered the ARV, therapy has been of exceptional significance to the society at large a lot of campaigns have been done encouraging infected people to use the drug. Patient’s adherence to this therapy has resulted in many lives being saved. Understanding and promoting adherence to antiretroviral medications in people living with HIV/AIDS is of enormous individual and public health significance. ARV has proved to be highly effective in reducing the viral load and associated morbidity of persons living with HIV/AIDS. It has played a significant contribution directly to dramatic declines in the HIV-related mortality. Given this deduction its substantial health benefits, it has subsequently reduced the expenses that would have or else been incurred by the victims and their families for medical bills purposes. It has also become easier and cheaper to access medical services. This factor in one way or another has highly contributed to the eradication of poverty since people living with HIV are still productive and a lot of resources are not being wasted for medical purposes. Despite all these positive facts, however, people using the drug have to change their lives in one way another particularly when it comes to matters of dieting and body exercises. Although computers are essential to the current day to day life I think life would still be impressive without them., Imagining that there would be other means of doing the things we do with a computer life would still continue normally but in a different manner. Supposedly if there was no internet, most probably people would have come up with another way of socializing to replace internet chatting. On the other hand, instead of writing emails letters would still be the main mode of communication for official matters. On the notion that computers have made the world a global village maybe there would other means that would be serving the same purpose.     

Isokinetic Devices Essay Example for Free

Isokinetic Devices Essay The word isokinetic is most commonly used in sports science and medicine. In these settings isokinetic defines a type of exercise or movement. Isokinetic movement is actually the opposite of isotonic movement which is probably the easiest way to think of it. Isotonic movement is the most common type of movement we human beings perform: Isotonic movement: In almost every situation, every day, we perform isotonic movements. In these types of movements we pick up a fixed weight, an empty pan basically anything that has weight. The weight of the pan is fixed but we decide how fast to lift it. We can lift it slow, fast, or anywhere in between. The key to this type of movement is we decide how fast it goes but the weight (resistance) remains constant. Isokinetic movement: In isokinetic movements the situation is reversed now we tell an isokinetic machine (the dynomometer) to move only at a certain speed (normally described in degrees per second). The machine will then vary its resistance against us to maintain that speed. This means if we push against the machine hard it will give back allot of resistance to maintain the speed it was told to go at. If we push or pull softly the machine reduces the weight to maintain the speed. To achieve isokinetic movement there are many different ways of developing the resistance, however, most people use an isokinetic device. Isokinetic devices are referred to as isokinetic machines and they vary vastly in technology and price. Most medical isokinetic machines are top of the range. They use a powerful motor to provide the isokinetic resistance to the force applied and then use a computer to keep the motion smooth, provide the acceleration and to record the results. In medical systems the components (the motor, gear box and computer control) are what make the machines so very expensive but they are also the parts that make them so very good. Other isokinetic machines use cheaper ways of developing the isokinetic motion. These methods include (but are not exclusively) hydraulic systems (water or oil commonly) clutch based systems (not really used anymore due to noise and running costs), friction based systems and elastic resistance machines. Advantages: * Maximal loading throughout whole range of motion. * Objective, reproducible and easily quantifiable. * Muscles easily isolated. * Safest form of exercise. * Few contraindications. Disadvantages: * Time consuming. * Requires a lot of training and skill to use. * Costly. * Results can be difficult to compare between machines. Other types of isokinetic / s: The most common isokinetic device used every day is a lift. Here no matter how many or few people get in the lift (which varies the resistance) the lift moves at a constant speed. Isokinetic is also be used in gas analysis: Isokinetic still means constant velocity or speed of motion but is used to describe the velocity of gas entering a sampler being the same as in a chimney or flue. Many isokinetic gas samplers work automatically. Two main types of equipment are produced: Automatic samplers used for dust and aerosol monitoring.

Marketing strategies which can help Cadburys in launching there new product

Marketing strategies which can help Cadburys in launching there new product Cadbury Background In 1824, John Cadbury began selling tea, coffee, and drinking chocolate, which he produced himself, at Bull Street in Birmingham, England. John Cadbury later motivated into the production of a variety of Cocoas and Drinking Chocolates being manufactured from a factory in Bridge Street, supplying mainly to the wealthy due to the high cost of manufacture at this time. At this time the company was known as Cadbury Brothers of Birmingham. Cadbury is a leading global confectionery company with an outstanding collection of chocolate, gum and candy brands. Cadbury employ around 45,000 people and has direct operation in over 60 countries, selling its products in markets everywhere around the world. Cadbury is nearly 200 years old. In 1969 Cadbury merged with Schweppes to create Cadbury Schweppes. In 2003, Adams Confectionery was acquired including its Trident and Halls brands, now respectively the worlds largest gum and candy brands. On 7 May 2008, Cadbury demerged the Americas Beverages business and created Cadbury plc. In March 2009, they announced a definitive agreement to sell the Australia Beverages business for approximately  £550 million. The following few pages which follow help to show overall how and which types of strategies on various things based on Marketing strategies can help Cadburys in launching there new product. Marketing strategy is a plan of action which is used by many businesses around the world, which helps the business meet its aims and objectives, it can also assist a business when launching a new product as it helps to identify which different strategies would be best to use. Marketing strategies can be split into two main categories which are: Short-Term Long-Term Short-term strategies help a business to focus mainly on the four Ps: Product, price, place and promotion which are vital to all businesses, as these four features are the main things which help a business to achieve objectives if they are used correctly. On the other we have long-term strategies which are used to plan the future actions of a business, this can include producing tables such as a Ansoff matrix which helps a business to decide on many things such as, whether to launch a new product or to improve previous products, overall making the right decisions on which type of strategy to use is vital, especially in the case of Cadburys as it helps to decide how to launch a new cereal bar, to ensure that they reach maximum sales. Throughout the next few pages I will discuss possible short-term and long-term strategies which Cadburys could use, indicating which type of strategy in each case would be the most useful to help them achieve success with there new product. Ansoff Matrix An ansoff matrix can be used to identify and show various types of growth strategies, many firms such as Cadburys could benefit from the use of an ansoff matrix as it helps to focus on the firms present and possible products as well as the markets. The main thing in ansoff matrix helps to identify is possible ways for a business to grow; this can include improving previous products or producing new products. Diversification Market Penetration: This is when a firm tries to achieve growth using existing products in there current market segment, to try and increase its market share. Product Development: This is when a firm targets a new product at there current market segment. Market Development: This is when a firm seeks growth by targeting there existing products at a new market. Diversification: This is when a firm tries to diversify into new businesses by producing new products to aim at a new market. Best marketing strategy for Cadburys: The following list helps to show which marketing strategy from the ansoff matrix would be best for Cadburys to use: If Cadburys was to use market penetration for there product, I feel this would not help at all as the current product they have out in the market which is the Brunchbar, is not doing very well and people would not buy it, so I feel this would be the worst option to choose. If Cadburys was to use product development for there product, I feel this could possibly be successful, although after the failure of there previous product people may not buy there new product. If Cadburys was to use market development, I feel that again there could possibly be a chance of success, as they may have aimed there previous product at the wrong market, although people from the new market may also not be keen to buy there product. It is clear that if Cadburys was to use diversification and aim a new product at a new market, there would be a high chance of success as long as the new product was to meet customer needs, which can be done through extensive market research to help gather an idea of people who would regularly purchase there product. Marketing Objectives Before a business such as Cadburys can decide on which market strategy they will be using, they must take into consideration that correct and precise marketing objectives are set to help the business to become as successful as possible in the future. The best way for a business to ensure that they set realistic and achievable objectives would be by following the acronym of SMART, this helps identify points which need to be checked by a business to make sure high-quality objectives are being set to maintain high sales for the product. The acronym SMART is short for the following which all need to be checked over by businesses when setting its marketing strategy: Specific Measurable Achievable Realistic Timed For a business such as Cadburys to be successful within such a competitive market, good quality objectives must be set. The following is a list of objectives Cadburys could set themselves to ensure that they are successful with the launch of there new product: Principles of Marketing There are many different features to be looked at when marketing your product to ensure there are no hiccups when releasing a new product. The following are a list of different things which need to be looked at by businesses such as Cadburys to ensure success for the new product: Understanding customer needs: This can be found through extensive market research to help the business determine the customers outlook on products and also the new tendency within the market. Through my market research which I have conducted, I have now found the correct segment for me to aim my product at helping to almost ensure success with the new product as I have covered the needs of my chosen segment. Understand and keep ahead of competitors: This again can be done through market research to help a business stay above competitors. I have used secondary research here to help me see the biggest rivalries within the market, therefore enabling me to stay above them. Communicate effectively with customers: This can be done through varieties of places; the most affective would be through promotional techniques used by the business. To ensure I have done this, I listed the possible promotion techniques and chose the ones which I felt would be best to use. Organize functions to achieve objectives: To ensure correct objective have been set, a business must look at the four Ps around the product to make certain that the correct marketing objectives have been set. To help me do this I ran through the four Ps of my product, and then checked to see that I had stated most of the possible strategies for the product. Aware of constraints: All businesses must be aware of the constraints they face on there marketing activities, to ensure that they are then able to work there way around it. To ensure I was aware of the possible constraints from many different factors, I produced both a SWOT and PEST analysis to help me identify these. The above principles of marketing must all be looked and analyzed by businesses, to ensure that the launch of the new product runs as smooth as possible. Cadbury plan their production process by using a time series method as this helps Cadbury to accurately produce the needed amount of chocolate at the correct period of time. A time series shows historical data that can be used and analyzed to predict future trends. Christmas and Easter are peak selling times for all chocolate manufactures including Cadbury; this is obviously because chocolate products make good gifts for these occasions. The disadvantages of this type of forecast are: Cadbury needs to have a lot of past data in order for the time series method to be used accurately to predict sales figures. If the external environment doesnt stay stable then there will be problems with the forecast for example if the prices of the raw materials used to produce Cadbury products increases then the price of the product has to increase in order for Cadbury to make a profit from the product produced. This may affect the customers purchasing trends. The data may be biased or representative. The advantages of this type of forecast are: The data helps Cadbury to reduce wastage and produce the amount of products that customers would purchase. The data is reliable if collected properly/accurately. The forecast helps Cadbury to make products efficiently as it helps Cadbury to set a target of the amount of products needed; there are always enough products to supply to customers. However precise information about this is not available to the public. Therefore I am going to use the information that I have produced about an imaginary firm I have used in E4 of my assignment. The most profitable product that the imaginary firm produces is the mugs, making a profit of  £10,500 for the first quarter of the year. I think that this is excellent as this firm is selling the mugs well and making a reasonable amount of profits from them; the mugs are batch produced and are everyday household objects. The firm does some research and find out what types of designs the customers are interested in purchasing. This would help to increase the sales, as customers like to have mugs with designs that they like and match with the rest of their kitchen accessories/items. If the firm shows that they are interested in giving the customers what they want then customers are very likely to purchase mugs from the firm. But a problem that would arise is that customers dont need too much mugs as they can be reused again and again so at some point the firm will need to stop producing mugs and withdraw it from the market as the demand will decrease. The firm could sell the mugs in multi packs as a set as well as individually and this will help to increase the sales of the mugs as most customers prefer to have a set of mugs the same design. From the figures of wastage and production I suggested that the saucer department of this firm should be closed down as it was costing the firm too much to continue to produce saucers to sell to the customers as it was not making its potential profit. The department that I suggested should have an increase in production was the teapot department this was due to the fact that it was the second most profitable product that this firm produced (along with the saucers but I have explained why it wasnt possible for the firm to continue to produce them). I think that if the firm improved the strength of the teapots then they would be more successful in the market as customers would realize this and want a teapot that is strong so it lasts longer. How the production process is monitored The quality assurance system that Cadbury use is total quality management (TQM). For Cadburys TQM is a method of ensuring that their products are of a high standard of quality and a method to monitor the production of products. To monitor the production process Cadbury employs supervisors to inspect the product at each stage of production. Marketing strategy In order to increase sales Cadburys needs to undertake a range of marketing activities before deciding upon the best way to encourage the purchase of its product. When identifying the basic principals which Cadburys must apply to its marketing will be its basic objectives because all business must have objectives it allows them to increase sales and make profit. Corporate aims are the long term intentions of a business, whereas corporate objectives are the specific targets required to achieve the aims. The common aim and objectives of the corporation such as Cadbury includes the following: Survival Profit maximization- which is often taken to be the reason why firms exists and to be the primary objectives in practices most firms have a hierarchy of objectives when a firms survival is threaten it may profit maximize in order to restore its financial health. Growth- which includes Cadbury selling new products or expanding overseas. Diversification- which is the spreading of business risks by reducing dependence on one product. Sales maximization- which is the increasing of sales Improving the product image-which includes creating a new logo or launching a new brand of product and creating more attractive packaging. For example, Cadbury set out two objectives for the development of their chocolate, Fuse. These were: To grow the market for chocolate confectionery To increase Cadburys share of the snacking sector when launching a product the company Cadburys had to make sure that any new product in the snaking sector must establish points of difference, creating a unique selling proposition (USP) i.e. a product with unique appeal which is not shared by any of its competitors. Referring back to the example of Fuse, Cadbury lost a lot of money testing out the combination of various ingredients and more than 250 were combined before the recipe of the chocolate was finalized. As the products are developed, Cadbury tests them to ensure that consumers are willing to buy them. Cadbury then promotes its products in various ways such as the use of above the line promotion, which is where a product is advertised through consumer media such as television, magazines, newspapers and radio. 4ps Product My product is a re-launch of Cadbury dairy milk. Cadbury dairy milk is made from real chocolate. Its ingredients include cocoa butter and there is a glass and half full cream dairy milk in every 200 grams of Cadbury dairy milk chocolate, Cadbury buys 65 million litres of fresh milk each year to make Cadbury dairy milk chocolate. Price Price is an important element of the marketing mix. The price charged for a chocolate bar can determine whether a consumer will buy it and the level of sales achieved can determine whether or not Cadbury Schweppes will make a profit. Price is also affected by factors such as the state of the economy, what competitors are charging, the stage reached in the products life cycle and above all what price the market will bear. From the marketing point of view this is what matters. Place Cadbury dairy milk is produced at the chocolate factory in Bourneville in Birmingham. After the chocolate is produced and has undergone all the quality checks it is transported to the stockrooms. After this Cadbury sells it products to shops that deal with beverages and confectionery e.g. corner shops, super stores such as Iceland, Sainsbury, Kwik save, Tesco, Asda, Safeway and petrol station. These businesses are usually visited by customers on a daily basis. They then sell it to the general public. Cadbury produces chocolate for more than 200 countries so that they have a chance to enjoy it as well and make profit. This gives them a wide range of consumers around the world. Cadbury Schweppes therefore makes sure that the cultures of these different people are kept. They can do this by producing products, which are eaten in that particular country without upsetting religious or cultural practices. Promotion The purpose of promotion is to communicate directly with potential or existing customers, in order to encourage them to purchase dairy milk and recommend it to others. The main promotional tools are sales promotions, public relations and advertising. Production representation Cadbury monitor the production process by using total quality management to ensure that the chocolate/products that are produced are of a high quality and meet the needs of the customers, this is vital for Cadbury because they produce chocolate products mainly which has a lot of substitutes, this means that customers could loose interest in Cadbury products if their demands are not met or thought about. To enforce total quality management Cadburys have supervisors that monitor the machines, the other workers and the products that are made. Cadbury also monitor the quality of their products by using a quality assurance system, (mentioned above) total quality management TQM. TQM ensures that the products that Cadbury produces tastes good to the customers, is appealing to the customers, customer complaints are solved, listening to customers and Cadbury make continuous improvements to their products. Those are all the benefits for Cadbury monitoring the quality of their products and usin g a quality assurance method. At the moment Cadburys use TQM to monitor the quality of their products and as a quality assurance method. I think that this could be improved if other methods of quality assurance and monitoring production were used; I think that this would help to improve them. An alternative quality assurance method that Cadbury could use is benchmarking. Benchmarking is a method for comparing the performance of one business against another, this would of an advantage to Cadbury because they could compare their sales figures, production figures etc against a major competitor (Nestle for example), the comparisons would help Cadbury to set aims and goals for the business itself and once the aims have been met it may almost be certain that Cadbury is outperforming its competitor. However the competitor that Cadbury choose has to be near enough the same size business as Cadbury, this is to make the benchmarking fair. As well as the above benchmarking will help Cadbury to do better than their competitor(s). To improve the monitoring method that Cadbury could use to monitor their products, Cadburys could continue to use total quality management ? TQM and also give all the other workers more responsibilities by enforcing self-checking and inspection on the products produced at Cadbury. Self- checking is traditionally the main method of a business to achieve quality control, to ensure that the workers inspect the products professionally, correctly and properly Cadbury should make a list of things that the workers should check. In 1895, an innovation in the provision of model housing by manufacturers occurred with the development by George Cadbury of Bournville Model Village. This was the first model settlement to provide low-density housing not restricted to factory employees. This paper uses the Bournville archives to explore the accepted history of this settlement. It is argued that the accepted history is a particular reading of this planning experiment. The paper explores the construction of the ‘accepted history, identifies some of the authors behind the history and uses the minute books and secretary reports of Bournville Village Trust to construct an alternative historical narrative. The alternative history is one in which Bournville begins as a building estate rather than as a model village. The building estate was provided with no community facilities, and the houses were targeted at the lower- and upper- middle classes. Cadbury repackaged the building estate by appropriating the garden city movement; in return the garden city movement also appropriated Bournville by using it as a working example of a model garden village. The paper makes a contribution to theoretical debate by linking a literature from organizational studies concerned with story-telling and construction to historical geography.

Analysis of SAMe as an Antidepressant

Analysis of SAMe as an Antidepressant S-Adenosyl-Methionine (SAMe) And Improved Methylation Offer A Serious Alternative To Orthodox Medications Can S-Adenosyl-Methionine (SAMe) and improved methylation offer a serious alternative to orthodox medications in the treatment of depression? Abstract In 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 characterise 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. Introduction In 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 aetiology 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 depression 1. Depressed mood for most of the day 2. Disturbed appetite or change in weight 3. Disturbed sleep 4. Psychomotor retardation or agitation 5. Loss of interest in previously pleasurable activities; inability to enjoy usual hobbies or activities 6. Fatigue or loss of energy 7. Feelings of worthlessness; excessive and/or inappropriate guilt 8. Difficulty in concentrating or thinking clearly 9. 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 weight 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 depression This 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 concentration 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 common 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. Fluoxetine 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 depression So 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 regulation 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 development 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 element 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 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 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 medication SAMe 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 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 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 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 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 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 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 that 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 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 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 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 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 levels 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 levels With 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 biochemical 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. Chemistry SAMe 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 reactions It 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 the 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 Analysis of SAMe as an Antidepressant Analysis of SAMe as an Antidepressant S-Adenosyl-Methionine (SAMe) And Improved Methylation Offer A Serious Alternative To Orthodox Medications Can S-Adenosyl-Methionine (SAMe) and improved methylation offer a serious alternative to orthodox medications in the treatment of depression? Abstract In 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 characterise 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. Introduction In 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 aetiology 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 depression 1. Depressed mood for most of the day 2. Disturbed appetite or change in weight 3. Disturbed sleep 4. Psychomotor retardation or agitation 5. Loss of interest in previously pleasurable activities; inability to enjoy usual hobbies or activities 6. Fatigue or loss of energy 7. Feelings of worthlessness; excessive and/or inappropriate guilt 8. Difficulty in concentrating or thinking clearly 9. 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 weight 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 depression This 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 concentration 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 common 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. Fluoxetine 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 depression So 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 regulation 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 development 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 element 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 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 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 medication SAMe 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 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 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 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 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 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 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 that 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 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 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 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 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 levels 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 levels With 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 biochemical 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. Chemistry SAMe 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 reactions It 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 the 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