S-Adenosyl-Methionine (SAMe) And Improved Methylation Offer A Serious Alternative To Orthodox Medications - Health Dissertations - Free Essay Example

Sample details Pages: 32 Words: 9620 Downloads: 8 Date added: 2017/06/26 Category Health Essay Type Research paper Did you like this example? 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 intera ctions 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 al though 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-I V) 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 diff icult 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 gen etic 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 rec orded 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 al so 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 l evels 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 Der ived 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. Man y 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 dep ression 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, i t 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 depressi on) 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 hyp othesis 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 B 12, 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 a ctivating 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 M AT (methionine adenosyl transferase) (Bigger et al 1990) As we have discussed, SAMe is a methyl donor. When it has donated its methyl group to the recipient molecule it becomes homocysteine. The cycle is completed when homocysteine (which is a methyl sink or potential recipient) accepts back a methyl group to become methionine once again. The relevance of this association of SAMe with homocysteine is of great importance, as homocysteine has recently become recognised as a source of major morbidity. High levels of homocysteine are associated with cardiovascular disease, hypertension and a number of degenerative illnesses. It is thought to be associated with a high incidence of spina bifida and a number of other neurologically based birth defects. High levels of homocysteine have been found in some cases of severe depression It is at this point that the significance of the relevance of folate and B12 becomes clear. It is one of the biochemical pathways that can supply methyl groups to homocysteine, thus detoxifying it. There are other potential pathways involving choline and other molecules but it is thought that the B12 and Folate pathways are the most clinically significant. Another way that homocysteine can be remethylated is through the mediation of B6 and magnesium. This allows the homocysteine to be converted back to the clinically safe cysteine. It may well be relevant, but we cannot find any work to support it directly, that methylation is also vital in the removal of many of the heavy trace metals that find their way into the body. This may well be relevant to our considerations here because it is well known that many of the heavy metal group are potent neurotoxins and neuroinhibitors. It is not surprising that such a centrally important molecule as SAMe is affected by a number of other clinically important molecules. B2, B6, B12 and folic acid deficiencies will all impair the ability of SAMe to be produced in sufficient quantities for optim um action. Equally it follows that SAMe is required to convert both folic acid and B12 to their active co-enzyme forms cyanocobalamin and methylcobalamin, both of which are important in maintaining the structural integrity of the myelin sheaths of the peripheral nerves and the membranes of the CNS neurones. We have discussed traumatic experience evidence for SAMe increasing the action of some of the neurotransmitters (specifically Noradrenaline, serotonin and dopamine). It appears to do this by improving or facilitating the binding mechanisms between these entities and the cell receptor sites. (Cohen et al 1989) It also appears to have a direct action on the neural cell membrane. Functionally it is not clear exactly what this action is, but structurally it increases the synthesis of a major structural ingredient of the membrane (phosphatidylcholine). By means of its ability to methylate enzymes, it is able to influence the production of polyamines which are vital in the pro cesses of phosphorylation of proteins within the CNS neurones. This appears to be a mechanism which is central to the mode of action of many of the more conventional categories of antidepressants. Brain tissue is unique amongst the tissues of the body in that it runs at 100% metabolic activity 100% of the time. Mitochondrial function is therefore vital to the integrity and continued proper function of the neurones. SAMe is necessary to maintain mitochondrial activity. It is theoretically possible that there is another pathway by which SAMe can influence depressive symptomatology. (Evans et al 1998) One other strand of evidence comes from the fact that the methylation process is important in the production of many of the anti-oxidants which are now realised to be vital in the protection of neural tissues. Specifically SAMe is vital to the production of glutathione which is a strong antioxidant and normally found in high concentrations in neural tissue. (De La Cruz et al 1992) Following our discussions so far we have to consider the issue of why is the process of methylation so important biologically? We have already examined the processes of pathway control by methylating (or activating) rate limiting enzymes. And we have mentioned the role of DNA and RNA in protein production. The process by which genes are switched on and off is, in part, a process of methylation. There is a genetic component in depression and therefore this becomes a relevant consideration (Janicak et al 1989) The methylation of cytosine is comparatively easily measured in biological samples and as such, it represents a marker for the methylation status of the body. At birth, a child has cytosine methylation rates of between 2-6% (range depends upon the particular type of cell measured). This is a reflection of the level of activity of the genes in the DNA which are currently active. In numerical terms the nuclear portion of the cells DNA would have about 90 million methyl gro ups. (Smith et al 1998). As life progresses, the reduction of the measurable levels of methylated cytosine is a measure of the ageing process. The cellular controls and the ability to access genetic information reduce as the methylation levels drop. Certain cancers seem to develop once the methylation level drops below about 80% of maximal methylation and auto immune diseases also appear to have a correlation with this level. It is postulated that depression might also be a part of this spectrum. For the record degeneration reaches a point which is incompatible with life once about 40% of the methyl groups in cellular DNA are lost Studies relating to SAMe efficacy as an antidepressant. Literature Review As we have commented above. SAMe became available for use on prescription in 1974. Since then a number of trials (of variable quality) have looked at its indices of action. One of the major clinical features of SAMe is the unusual speed of onset of action when it is co mpared to other antidepressants. For reasons that we have explored above, most of the other antidepressants would not be expected to exert any significant beneficial effect until about two or three weeks after beginning the course at a therapeutic dose. Faya (et al 1995) looked at enhancing the speed of onset of action by using SAMe parentally. The trial design was neither blinded nor controlled as it was a simple study of 195 patients receiving the drug by this method. The authors observed that a measurable response was found to the extent that the symptoms remitted between 7 and 15 days. This particular trial is not very satisfactory, not only for the reasons of trial design mentioned above, but also because the authors do not tell us how they measured the degree of resolution of the symptoms. They did however, comment on the fact that even when giving the patients a comparatively large dose (400mg IM) they found no evidence of serious adverse effects. One way to avoid the s hortcomings of small cohorts in a trial is to perform a meta-analysis of a number of trials. Bressa (1994) provided us with the most recent reliable work in this respect. He conducted a meta-analysis of all of the major double blind placebo controlled trials that had been published up to that date. One of the problems that he experienced was that different trials defined their particular endpoint in different ways. For that reason he gives the overall response rate as between 17 and 38% (when compared to placebo results), and the degree of the response is comparable to that of the tricyclic group of antidepressants. Bottiglieri (et al 1994) (I) produced a paper which gave an overview of the currently known activity and significance of SAMe in the neuropsychiatric disorders. It covers much of the same ground that we have already explored above but it is significant in that it refers to evidence that deficiencies of both Vit B12 (cyanocobalamin) and folate have been found to be ass ociated with reductions in the concentrations of SAMe in the CSF. Sadly he does not give any references to where he found this information so we cannot check its credentials. He does, however, draw attention to the fact that it is well known that deficiencies of both cyanocobalamin and folate are associated with a number of other neurological manifestations, namely depression myelopathy, a number of forms of dementia and peripheral neuropathy. He comments on the fact that it is unlikely to be a coincidence that the metabolic pathways of these substances are intimately related to those of SAMe and that SAMe is demonstrated to be of clinical value in depression and some forms of dementia insofar as it can improve their cognitive function. It equally follows that the same statement is true when you consider the fact that treatment with methyl group donors (such as SAMe ) are found to be beneficial in treating the demyelination effects of the inborn errors of metabolism that involve both the folate and C-1 pathways. In contrast to the Faya study mentioned above, the study by Bell (et al 1994) was fastidious in both its design and execution. It was a double blind randomised medication comparison (desipramine) trial with clearly defined entry and exit points. It chose to compare the relationship between plasma levels of SAMe and the clinical response that was found in patients who had a major depressive illness. The only significant criticism that one could reasonably level at this particular trial structure was that it had a small entry cohort of only 26 patients. Given the fact that each required a huge amount of input it is not really surprising that there were not many, but the fact of the matter is that it is difficult to get statistically significant results from such a small cohort. The results were really both impressive and significant. In terms of clinical response. In terms of clinical response the authors found that at the end of the 4 week tria l 62% of the SAMe treated patients had significantly improved. The definition of improvement was given as a 50% decrease on the Hamilton Depression Rating Scale (HAM-D). This compares with the 50% improvement found with the desipramine group. So in this respect, SAMe compared favourably with desipramine. The really significant finding from this trial, at least in the context of this dissertation, was the fact that regardless of which medication the patients were given (either SAMe or desipramine), the ones that did respond were found to have a significant increase in the blood levels of SAMe. This is very good evidence that there is a direct correlation between the degree of improvement of severely depressed patients and the blood levels of SAMe, irrespective of the treatment type. This strongly suggests that SAMe has a major role in the determination and control of mood. This is possibly one of the strongest pieces of evidence that we have found, in terms of hard demonstrable fa ct, that SAMe does have a place in the treatment of depressive states. This finding is expanded further by Bottiglieri (1994) (II) who writes another review of the current knowledge relating to SAMe. In this review he takes a slightly different, neurological perspective. He points to evidence which shows that although there is no consistent evidence to link SAMe with psychiatric illness, low levels of SAMe in the CSF have been found in patients with other neurological deficits such as Alzheimers Disease, subacute combined degeneration of the spinal cord (SACD) and some of the HIV associated neuropathies. Other studies have also been able to demonstrate the finding that SAMe levels are low in patients who have suffered depression. (Johnstone Stevens 1992). The same study also found that the enzyme MAT (which catalyses the reaction between methionine and ATP to produce SAMe) was found to be low when assays were done on the red blood cells of depressed patients. Further evide nce comes from the paper by Baldessarini (1987) in which the authors found that SAMe has low levels in dementia alcohol abuse and increasing age. This point may well be relevant insofar as it is well known that patients who are depressed are more likely to use alcohol as a means of mediating their symptoms. The fact is that this actually worsens their overall condition. An excess of alcohol interferes with the production of SAMe. The situation is compounded by the fact that SAMe is required in the liver to provide the methyl groups necessary for the methylisation and detoxification of alcohol. In short, alcohol reduces the levels of SAMe which are therefore not available to detoxify the alcohol. This can result in liver damage. The lowering of the SAMe levels increases the tendency to clinical depression and therefore the patient will often feel the need to drink more, and so the cycle continues.. (Reid Reynolds 1994). This is really a very well written, researched and complex p aper which we have, (for obvious reasons), extracted the relevant pieces of information that are strictly relevant to this dissertation. In the paper by Flynn (et al 1994) it has is reported that giving SAMe supplements to these patients not only appears to protect the liver against the toxic effects of alcohol, but it also can reduce alcohol-related depression. (Kegan et al 1990) Trials have also been done in the depressive states that can frequently accompany Alzheimers Disease. In this condition, SAMe blood levels can be very low to the point where they can be almost undetectable. (Smythe 1998) Morrison ( et al 1996) found that SAMe can produce small, but measurable, improvements in the depressive score ratings of some patients with Alzheimers Disease . In terms of efficacy, there is plenty of evidence to show that SAMe is superior to placebo, but few well constructed trials have sought to demonstrate that it is actually as good as, or perhaps superior to conventional medications. (Rudoref et al 1989) compared SAMe to a number of other antidepressants currently in use at the time. His results show that SAMe was at least equal to, and in some instances superior, to imipramine (a tricyclic antidepressant). This particular paper reports the results of a number of smaller separate trials, all of similar design. It has to be said that the entry cohort for each were actually very small and therefore proper statistical significance cannot really be applied to these reported findings. (Kegan et al 1990) found that patients who did not respond well to mainline antidepressants or alternatively had unacceptable side effects, could have a good response with SAMe. Again, the numbers involved were comparatively small. Conclusions and Discussion Throughout the dissertation we have been endeavouring to answer the question Can S-Adenosyl-Methionine (SAMe) and improved methylation offer a serious alternative to orthodox medications in the treatmen t of depression? From the evidence that we have assembled it would appear that the answer is a qualified Yes. There is little doubt that examination of the evidence that we have for the neuroactivity of SAMe suggests that it is certainly a good candidate for influencing the neural pathways that control and regulate mood. From both a theoretical and a practical perspective we can see that it probably SHOULD work. As with most things in the field of pharmaceuticals, there is a huge gulf of difference between thinking that something should work, and the reality of it producing good, consistent and safe results in the patient. SAMe was discovered in 1952 as a chemical entity, but it was not until 1974 that it was first produced on a commercial scale for human therapeutic use. This represents the fact that initially, nobody saw its potential as a therapeutic agent. As its chemistry was better understood, it was appreciated that its function was central to many of the vital rate lim iting processes within the cell. The decision was taken to promote it as a therapeutic agent in several different therapeutic fields, and the hugely expensive mechanism of getting pharmacological approval was initiated. It is noted that it was originally investigated and approved in Italy, and this is the reason for the fact that the majority of the early work has Italian authorship. In 1974, initial approval was granted and large scale trials began. In this dissertation we have discussed the evidence that SAMe is effective in cases of depression. A considered overview of all of the available evidence would have to conclude that it does not appear to have any significant therapeutic advantage over any of the other currently available antidepressants in terms of efficacy. The majority of the studies that have compared SAMe with another agent have shown that both work better than a placebo with a few percentage points difference between them. Almost without exception, the studie s that have been reviewed are really quite small in terms of entry cohort and therefore are not suitable for major extrapolations in terms of efficacy comparisons. The two meta-analyses that we have presented are also flawed in this respect and although positive trends can be identified, the statistical validity is certainly not up to the standards that we would expect if they were published in a contemporary peer reviewed journal today. Where SAMe does appear to have a major clinical benefit over its competitors is in its side effect profile. It does appear to be extraordinarily safe and free from significant side effects. The only real contraindication that we have seen is when it is being considered in patients who have a history of mania or in the presence of bipolar disorder. Even then, it does appear to be a comparatively unusual event. Some studies have reported nausea. This is thought to be a centrally mediated effect as it has been shown to exert a protective effect on t he gut lining having been used, transiently, as an ulcer-healing agent. In terms of specific types of depression, we have presented evidence that SAMe appears to work in certain types of depressive states more predictably than in others. It seems to be at its most useful therapeutically, in states of primarily endogenous depression. To a lesser degree it has an effect in those depressive states which can be associated with the degenerative dementias. There seems to be little direct evidence that it has a significant effect in the reactive forms of depression. From what we know about the neuropharmcology of SAMe, this would appear to be both logical and, to an extent, predictable. As far as the endogenous depressions are concerned, it is thought that they are primarily caused by various metabolic disturbances within the neuronal pathways of the brain. We know that, on a simplistic level that this is where SAMe has its prime effects. We know that it has various trophic effects on the neuroexcitatory pathways and it does therefore not require a huge leap of faith to see that it could work in these situations. Reactive depression is not thought to be a straightforward chemical abnormality in the brain, but it a reaction to external events, and therefore is more likely to be mediated by inhibitory triggers coming from the higher intellectual centres in the brain possibly working through the hippocampus. Again, it does not require a huge insight to appreciate that SAMe might be less effective in those circumstances. Many of the degenerative dementias are thought to be due to (in part) a failure of the methylating processes in the neural tissues. These are generally associated with neuronal destruction, so significant improvement in cognitive function simply would not be expected. From the evidence that we have seen, it appears that SAMe is capable of exerting a minor degree of positive change in mood states in some cases of dementia, but it is clearly not the degree of response that we have seen in the more straightforward endogenous depressive states. In summary, SAMe does appear to offer a serious alternative to orthodox medications in the field of depressive illness. As with all therapeutic agents, the science of pharmacology is knowing about the nature of the drugs, the art of using them is to make correct judgements about the type of patient who is likely to respond to them. References Altar, C. A. (1999) Neurotrophins and depression. Trends in Pharmacological Sciences, 20, 59-61. Bazin, N., Perruchet, P., De Bonis, M., et al (1994) The dissociation of explicit and implicit memory in depressed patients. Psychological Medicine, 24, 239-245. Baldessarini, R.J. (1987) Neuropharmacology of S-adenosyl-L-methionine Ann J Med 83(Suppl 5A): 95-103 Bell KM, Potkin SG, Carreon D, Plon L 1994 S-adenosylmethionine blood levels in major depression: changes with drug treatment. Acta Neurol Scand Supp l 1994;154:15-8 Berlanga C, Ortega-Soto HA, Ontiveros M, Senties H 1992 Efficacy of S-adenosyl-L-methionine in speeding the onset of action of imipramine. Psychiatry Res 1992 Dec;44(3):257-62 Bigger et al 1990 Neuroendocrine effects of SAMe, a novel putative antidepressant J Psychiatr Res, 1990, 24:2. Bottiglieri T, Hyland K, Reynolds 1994 (I) The clinical potential of ademetionine (S-adenosylmethionine) in neurological disorders. Drugs 1994 Aug;48(2):137-52 Bottiglieri T, Hyland K 1994 (II) S-adenosylmethionine levels in psychiatric and neurological disorders: a review. Acta Neurol Scand Suppl 1994;154:19-26 Breggin, P.R. 1994 Talking Back to Prozac NYC: St. Martins Press, 1994. Bressa, G.M. (1994) S-adenosyl-L-methionine (SAMe) as antidepressant: meta-analysis of clinical studies Acta Neurol Scand: Suppl 154: 7-14 Carney MW, Edeh J, Bottiglieri T, Reynolds EM, Toone BK 1986 Affective illness and S-adenosyl methionine: a p reliminary report. Clin Neuropharmacol 1986;9(4):379-85 Carney, M.W. et al (1987) S-adenosylmethionine and affective disorder Ann J Med 83(Suppl 5A) 104-06. Caruso, I. Pietrogrande, V. (1987) ..Comparing [SAMe], naproxen and placebo in the treatment of degenerative joint disease Ann J Med 83 (Suppl 5A): 66-71. Cohen BM, Stramentinoli G et al. 1989 Effects of the novel antidepressant SAMe on alpha-I and beta adrenoceptors in rat brain. Eur J Pharmacol, 1989, 170(3):210-207. Cooper, J.R., Bloom, F.E. Roth, R.H. 1999 The Biochemical Basis of Neuropharmacology NYC, Oxford: Oxford Univ. Press, 1999 Czyrak A, Rogoz Z, Skuza G, Zajaczkowski W, 1992 Antidepressant activity of S-adenosyl-L-methionine in mice and rats. J Basic Clin Physiol Pharmacol 1992 Jan-Mar;3(1):1-17 Dallman, M. F., Akana, S. F., Cascio, C. S., Darlington, D. N., Jacobson, L.,Levin, N., 1987. Regulation of ACTH secretion: Variations on a theme of B. Recent Prog H orm Res 43: 113-173 De La Cruz JP et al. 2000 Effects of chronic administration of SAMe on brain oxidative stress in rats. NaunynSchmiedebergs Arch Pharmacol, 2000, 361(l);47-52 Drevets, W. C., Price, J. L., Simpson, J. R., et al (1997) Subgenual prefrontal cortex abnormalities in mood disorders. Nature, 386, 824-827 Duman, R. S., Heninger, G. R. Nestler, E. J. (1997) A molecular and cellular theory of depression. Archives of General Psychiatry, 54, 597-606 Evans et al 1998 Total serum homocysteine in senile dementia of Alzheimers type. Int J Geriatr Psychiatry 1998, 13(4):235-239. Fava M, Giannelli A, Rapisarda V, Patralia A, Guaraldi 1995 (I) Rapidity of onset of the antidepressant effect of parenteral S-adenosyl-L-methionine. Psychiatry Res 1995 Apr 28;56(3):295-7 Fava M, Rosenbaum JF, MacLaughlin R, Falk WE, Pollack MH, Cohen LS, Jones L, Pill L (II) 1990 Neuroendocrine effects of S-adenosyl-L-methionine, a novel putative anti depressant. J Psychiatr Res 1990;24(2):177-84 Flynn 1994 SAMe in the treatment of major depression complicating chronic alcoholism Curr Ther Res Clin Exp 1994,55:1. Gold PW, Goodwin FK, Chrousos GP, 1988. Clinical and biochemical manifestations of depression. Relation to the neurobiology of stress N. Eng. J. Med. 319:413-420. Gould, E., Tanapat, P., McEwen, B., et al (1998) Proliferation of granule cell precursors in the dentate gyrus of adult monkeys is diminished by stress. Proceedings of the National Academy of Sciences of the USA, 95, 3168-3171. Harmer, S. A. Hill, M. J. Taylor, P. J. Cowen, and G. M. Goodwin 2003 Toward a Neuropsychological Theory of Antidepressant Drug Action: Increase in Positive Emotional Bias After Potentiation of Norepinephrine Activity Am J Psychiatry, May 1, 2003; 160(5): 990 992. Henke, P. G. (1990) Granule cell potentials in the dentate gyrus of the hippocampus: coping behaviour and stress ulcers in rats. Beha vioural Brain Research, 36, 97-103 Johnstone Stevens 1992 SAMe as an antidepressant. New Trends Clin Neuropharmacol 1992, 6:1-4. Kalin, N. H., Dawson, G., Tariot, P., Shelton, S., Barksdale, C., Weiler, S.,Thienemann, M., 1987. Function of the adrenal cortex in patients with major depression. Psy Res 22: 117-125. Kathol RG, Jaeckel RS, Lopez JF, Meller WH, 1989. Pathophysiology of HPA axis abnormalities in patients with major depression: an update. Am J Psychiatry 146:311-317. Kagan BL, Sultzer DL, Rosenlicht N, Gerner RH 1990 Oral S-adenosylmethionine in depression: a randomized, double-blind, placebo-controlled trial. Am J Psychiatry 1990 May;147(5):591-5 Kegan B et al. 1990 Oral SAMe in depression: a randomized, double blind, placebo-controlled trial. Am J Psychiatr 1990, 147:591-595. Kendler KS, 1998. Major depression and the environment: a psychiatric genetic perspective Pharmacopsychiatry 31(1):5-9 LeDoux, J. (1996) The Emotional Brain. New York: Simon and Schuster. 1996 Levine, E. S., Crozier, R. A., Black, I. B., et al (1998) Brain-derived neurotrophic factor modulates hippocampal synaptic transmission by increasing N-methyl-D-aspartic acid receptor activity. Proceedings of the National Academy of Sciences of the USA, 95, 10235-10239 Lopez, J. F., Chalmers, D., Little, K. Y.,Watson, S. J., 1998. Regulation of 5HT1a receptor, glucocorticoid and mineralocorticoid receptor in rat and human hippocampus: Implications for the neurobiology of depression. Biol Psychiatry 43: 547-573 Lopez, J. F., Liberzon, I., Vazquez, D. M., Young, E. A.,Watson, S. J., 1999 (I) Serotonin 1a receptor mRNA regulation in the hippocampus after acute stress. Biological Psychiatry 45: 943-947. Lopez, J. F., Akil, H.,Watson, S. J., 1999 (II) Neural circuits mediating stress and anxiety. Biological Psychiatry 1999 Janicak PG, Lipinski J et al. 1989 Parenteral SAMe in depression. lit erature review and preliminary data. Psychopharmacol Bull 1989,25(2):238-242. Mathews, C. van Holde, K. 1990 Biochemistry, pp. 708-15. Redwood City CA: Benjamin/Cummings Pub., 1990. Melzter H, 1989. Serotonergic dysfunction in depression. Br J Psychiatry 155:25-31. Morrison et al, (1996) Brain [SAMe] levels are severely decreased in Alzheimers disease Neurochem 67, 1328-31. Murphy BEP, 1991. Steroids and Depression. J Steroid Biochem 38:537-559 Nemeroff, C. B., 1998. The neurobiology of depression. Sci Am 278: 42-49 Peinell and Smith 2003 Treatment Complementary Health Practice Review, April 1, 2003; 8(2): 99 115. Post RM. 1992. Transduction of psychosocial stress into the neurobiology of recurrent affective disorder. Am J Psychiatry 149:999-1010 Reid Stewart 2001 How antidepressants work New perspectives on the pathophysiology of depressive disorder The British Journal of Psychiatry (2001) 178: 299-303 Reid Reynolds 1994 SAMe in the treatment of major depression complicating chronic alcoholism Curr Ther Res Clin Exp 1994,55:1. Reynolds et al, (1984) Methylation and mood Lancet II, 196-98. Robertson, J. Monte, T. 1997 Natural Prozac San Francisco: Harper, 1997. Rosenbaum JF, Fava M, Falk WE, Pollack MH, Cohen LS, Cohen BM, Zubenko GS 1990 The antidepressant potential of oral S-adenosyl-l-methionine. Acta Psychiatr Scand 1990 May;81(5):432-6 Rudoref MV, Potter WZ. 1989 Antidepressants: A comparative review. Drugs 1989, 7(5):713-738. Saarelainen, P. Hendolin, G. Lucas, E. Koponen, M. Sairanen, E. MacDonald, K. Agerman, A. Haapasalo, H. Nawa, R. Aloyz, P. Ernfors, and E. Castren 2003 Activation of the TrkB Neurotrophin Receptor Is Induced by Antidepressant Drugs and Is Required for Antidepressant-Induced Behavioral Effects J. Neurosci., January 1, 2003; 23(1): 349 357. Salmaggi P, Bressa GM, Nicchia G, Coniglio M, La Greca P, Le Graz ie C 1993 Double-blind, placebo-controlled study of S-adenosyl-L-methionine in depressed postmenopausal women. Psychother Psychosom 1993;59(1):34-40 Shah, P. J., Ebmeier, K. P., Glabus, M. F., et al (1998) Cortical grey matter reductions associated with treatment-resistant chronic unipolar depression. Controlled magnetic resonance imaging study. British Journal of Psychiatry, 172, 527-532 Siuciak, J. A., Lewis, D. R., Wiegand, S. J., et al (1997) Antidepressant-like effect of brain-derived neurotrophic factor (BDNF). Pharmacology, Biochemistry and Behavior, 56, 131-137 Skolnick, P. (1999) Antidepressants for the new millennium. European Journal of Pharmacology, 375, 31-40. Smith, M. A., Makino, S., Kvetnansky, R., et al (1995) Stress alters the expression of brain-derived neurotrophic factor and neurotrophin-3 mRNAs in the hippocampus. Journal of Neuroscience, 15, 1768-1777 Smith and Blackwood 2004 Depression in young adults Advan. Psychi atr. Treat., January 1, 2004; 10(1): 4 12. Smith Harriman 1998 Review article Journal Medical Hypothesis (Vol. 51, pages 179-221, 1998) Smythe 1998 Total serum homocysteine in senile dementia of Alzheimers type. Int J Geriatr Psychiatry 1998, 13(4):235-239. Stewart, C. Reid, I. (2000) Repeated ECS and fluoxetine administration have equivalent effects on hippocampal synaptic plasticity. Psychopharmacology, 48, 217-223 Stramentinoli, G. (1987) Pharmacologic aspects of [SAMe] Ann J Med 83 (Suppl 5A): 35-42. Thomas CS, Bottiglieri T, Edeh J, Carney MW, Reynolds EH, Toone BK 1987 The influence of S-adenosylmethionine (SAM) on prolactin in depressed patients. Int Clin Psychopharmacol 1987 Apr;2(2):97-102 Vaidya, V. A., Siuciak, J. A., Du, F., et al (1999) Hippocampal mossy fiber sprouting induced by chronic electroconvulsive seizures. Neuroscience, 89, 157-166 Zuess J 2003 An Integrative Approach to Depression: Part 1Etiology Co mplementary Health Practice Review, January 1, 2003; 8(1): 9 24. Don’t waste time! Our writers will create an original "S-Adenosyl-Methionine (SAMe) And Improved Methylation Offer A Serious Alternative To Orthodox Medications Health Dissertations" essay for you Create order

The Decline of Education in America Essay - 3403 Words

The quality of education given in todays schools has declined since the idea of schools began. Currently students are graduating without being able to read or write. The blame lies on the teachers, government and every American citizen for not speaking up to bring change sooner. Only in the most recent years has there been any will to change the system.(Sharma) It is argued that there are 4 elements critical to the effectiveness of the instructional process: 1. the learner, 2. the teacher, 3. the home, and 4. the academic programs and the physical facilities at the school. These are interdependent and interactive and must function in unison for effective teaching to take place. The teachers primary responsibility is to help†¦show more content†¦Some schools are so out of control that some teachers are afraid for their lives, not to mention the students. How can a student learn if they think they might be killed after class or offered drugs? The United States needs to stop sending money to other countries and start spending money on the future leaders of this country. The teacher plays the most vital role in education, without their involvement, no learning would exist. Currently the qualifications for teaching are fairly adequate. One serious problem is the salary for teachers and how highly they are respected by society. As of now, garbage collectors and paid more than teachers. Its as if Americans want clean neighborhoods more so than they do educated children. Why should a teacher be compelled to teach if they dont get much respect for it? Most teachers are what they are by a choice and a desire to educate. Most garbage collectors did not chose to be what they are, its just a matter of circumstances. Being a teacher is not a 9-5 job. Teachers may work from 9-4 or 9-9, they have a very demanding schedule and work different lengthy hours for the same wage. If teachers are paid more, they are likely to teach better. 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Exploring The Novel Poisonwood Bible And Macbeth English Literature Essay Free Essays

The drama Macbeth by William Shakespeare and the fresh Poisonwood Bible by Barbara Kingsolver, are literary plants that explore the deep desires of self fulfilment. While many different literary devices are outstanding in both plants, this paper will concentrate on the intervention of subjects by both writers. Namely the subjects of power and control. We will write a custom essay sample on Exploring The Novel Poisonwood Bible And Macbeth English Literature Essay or any similar topic only for you Order Now These subjects are best highlighted in Lady Macbeth from Macbeth and Nathan Price from the Poisonwood Bible. These two characters best develop the subjects of power and control through their shared features of aspiration, use and pitilessness. Ambition is a reoccurring tool of character development in both The Poisonwood Bible and Macbeth, employed by the writers to stress the overall subjects of power and control. Nathan is a clergyman from America in the Congo trying to conform the small town of Kilanga to the Catholic religion. His aspiration and motivations are powered by fright and blind religion in God, coupled with desire for personal power-which he self interestedly translated into taking control of the small town and holding power over the people. He besides believes that if he does non finish the undertaking he will be unable to come in heaven. His aspiration begins to over power his judgement, his ability to ground and his construct of household, which causes the small town people to beat up against him to seek and re derive their freedom and independency hence exercising their ain signifier of power and re-enforcing the overall subjects. Unlike Nathan ‘s gradual and increased aspiration, Lady Macbeth â₠¬Ëœs aspiration is instantly apparent from the beginning of the drama, and merely grows as the desire for the throne and its power direct her over the border. She right off begins to piece a program to kill King Duncan in order to put her hubby Macbeth in line for the throne. This compulsion drives her insane, and like Nathan her ability to ground, her judgement and her scruples are clouded by her demand for power and control. She acted in ways that showed that she would halt at nil in order to derive the throne even if it meant slaying. Both characters became so ambitious in their efforts to derive power and wield control, that it finally drives them to their ain deceases. Manipulation is another changeless, though more subtly employed, word picture tool in both plants. She manipulated Macbeth into killing Duncan, in order to derive the rubric of King and Queen. Lady Macbeth ironically, felt excessively guilty to kill Duncan herself-due to resemblance to her father-however, had no scruple or concern for Macbeths witting when she manipulated him into killing his friend. In order to carry through this she began oppugning Macbeth ‘s manhood, seeking to convert him that he was emasculate -hence weaker so she, so she and that he could non step up to the undertaking of killing Duncan. This mental use made him oppugn his judgement, which led to him going really baffled. In the terminal her uses were successful, assisting her achieve the power and control she so greatly desired. Nathan like Lady Macbeth, abused his household in order to acquire what he wanted. The villagers had become so fed up with Nathan seeking to command them and their faith that the y rebelled, killing all the white people in their small town. Nathan ‘s married woman and kids are in secret fixing to get away to America, but Nathan, out of fright of solitariness, begins to mistreat and pull strings his married woman, and endanger the lives of his kids, in order to acquire them to stay in the small town and let him to go on his quest. This maltreatment and use allowed Nathan to recover power and control over his household, while doing them even more anguish as they impotently watch the deceases of many people they loved. Both Lady Macbeth and Nathan ‘s uses and evident deficiency of guilt over them, show to the audience merely how pitiless both characters are. This pitilessness is a 3rd of import manner the characters are both developed and the subjects enriched. Nathan is so determined to complete the quest God sent him to make that he forgot his ethical motives and committed awful Acts of the Apostless in order to obtain power over the small town people and control over his household ensuing in the loss of many guiltless lives. His chief distressing act of pitilessness was working his girls and coercing them to remain in the Congo so that he could keep his control over them while the villagers fought for their freedom. These egoistic actions resulted in the decease of his four girls and married woman, go forthing him entirely. Lady Macbeth was far more pitiless so Nathan, upon hearing that Macbeth was to be king she immediately began to inquire God to do her into more of a adult male in order to be able to perpetrate slaying. â€Å" Come, you spirits that tend on moral ideas, unsex me here, aˆ?aˆ?And make full me, from the Crown to the toe, Top-full of direst inhuman treatment. aˆ?aˆ?A Make midst my blood. â€Å" ( Lady Macbeth- Act 1 scene V ) . She lost her scruples wholly and began to move without witting in the effort to derive the throne, her symbols of power and control. Lady Macbeth increasingly becomes more pitiless, until she does non even question the idea of killing Duncan in order to be following in line to the throne, she is over whelmed in her ain desires, that she forgot about everything else that use to affair. Throughout both Macbeth and the Poisonwood Bible both writers develop their several characters of Lady Macbeth and Nathan Price by foregrounding their picks and actions through aspiration, use and pitiless action. These characters therefore serve to foreground the overall subjects of power and control in both plants. Both Nathan and Lady Macbeth sacrificed everything for power and control non recognizing the true cost. Nathan losingss his full household and is left to populate entirely, and Lady Macbeth looses her saneness, driving herself to take her ain life. Their battle for power and control wrecked many lives and in the terminal their several triumphs was so little that it all did non look worth the attempt. COMPARATIVE ESSAY Having†¦ Lady Macbeth from Shakespear ‘s Macbeth and Nathan Price from the Poisonwood Bible By: Tori Skot For: Ms.Zaikos January 7, 2008 How to cite Exploring The Novel Poisonwood Bible And Macbeth English Literature Essay, Essay examples

Business Risk HIH Insurance Limited

Question: Discuss about the Business Risk for HIH Insurance Limited. Answer: Introduction: The overall study mainly helps in evaluating the case study of HIH Insurance limited and the fraud conducted by the directors of the company. In addition, the study effectively depicts different types of risk that was associated with the business assessment of HIH insurance limited. Moreover, the novice effectively provides details about the inherent risk that contributed in the collapse of HIH Insurance Limited. In addition, the study provides details about the legal liabilities, which might be enforced on to the directors of HIH Insurance for purposely using unethical means in their organisations to support their activities. Lastly, the novice depicts the ethical considerations, which could be conducted by HIH Insurance before increasing its risk exposure. Inherent and Business Risk Assessments Assessing the business risk of HIH insurance Limited: The main business risk that surrounded the overall operations of HIH Insurance is the insolvency and business structure risk. Sadgrove (2016) stated that insurance companies use low risk profile, where the return is high and risk of loss is relativity low. The assessment of HIH Insurance business risk is as follows. Insolvency risk: Moreover, the overall insolvency risk of HIH insurance company mainly relied on the auditing risk conducted by the auditor of the company. In addition, the balance sheet of the company mainly comprises of data, which reduces the overall debt of the company. In addition, the balance sheet manipulation reduced debt ratio and portrayed wrong valuation of the company. Michelacci and Schivardi (2013) stated the indentified loopholes in accounting are used by companies to inflate their balance sheet and attract potential investors. Organisational structure risk: HIH Insurance mainly changed its risk by entering into the high-risk insurance arenas like marine aviation, natural disasters, and film financing insurance. In addition, the risky endeavours of HIH Insurance mainly increased their losses. In addition, the current organisational structure of the insurance sectors mainly excluded these arenas, which was targeted by HIH Insurance. Grant et al. (2014) argued that without attain risk high return from investment could not be achieved. In addition, the higher risk structure adopted by HIH Insurance mainly increased their overall loses to $100 million from film insurance. In addition, HIH insurance did not upheld the rules and regulation laid down by Australian Prudential Regulatory Authority (APRA) in commencing their business activities. Depicting different inherent risk factors that affect HIH at financial report level and evaluating the increase or decrease in inherent risk: The overall inherent risk factors mainly comprises of the misstatement in financial report of the company. In addition, the inherent risk mainly reduces the authenticity of the financial report, which might be used by investors to evaluate the solvency status of the company. Faria et al. (2013) argued that companies with the help of auditors are able to misstate or omit their liabilities in financial report, which in turn could portray solvency of the company. Moreover, the inherent risk of HIH insurance would be according to the relative insurance companies. However, the auditors did not address the involvement of the company in marine aviation, natural disasters, and film financing insurance, which might increase the overall inherent risk. In addition, the control risk and risk detection of the company lost their friction used to the involvement of the company in higher risk insurance arenas. Moreover, the control risk mainly helps in depicting the inaccuracy conducted by the company in their financial statements. However, the accommodation of risky activities mainly decreased the efficiency of the inherent risk adopted by the auditors. Moreover, the risk detection method used by the auditors mainly decreased due to the implementation of reinsuring policies used by HIH for ordinary policies and providing higher risk insurance schemes. Mellichamp (2013) stated that auditors to increase their personal income use unethical measures and help companies to inflate their overall balance sheet. Legal Liability Evaluating the facts and findings of relevant court cases that might help Andersen to determine the likelihood of partnership for clients and creditors: The case of HIH insurance scandal might be depicted an adequate relevant court case, which might be referred by Anderson in analysing the likelihood of partnership of Clients and creditors. Moreover, the court mainly banned the directors for 10 years on the ground off fraud and instructed to pay a compensation of $7 million. Arlen and Carney (2012) argued that without the insolvency declaration it is hard for investors to detect the fraud conducted by companies in their annual report. Clients perspective: The clients of HIH Insurance mainly Mr. Brad Cooper was involved in unethical activities to bribe the agent of HIH for insuring higher risk assets. In addition, the HIH investigation member mainly received $124,000 indirectly or directly to allow the payment of $737,000. Moreover, these criminal activities conducted by the company were held in court, which helped in proving their guilt. Brochet and Srinivasan (2014) argued that unlawful sum of gifts are received by companies heads to allow unjustified insurance claims of their clients. Creditors perspective: Mr. Stephen Burroughs an office of the FAI General Insurance Company limited a creditor of HIH Insurance mainly was committed on trial charges falling to act honestly in portraying the unethical measures conducted by HIH insurance company. Mr. Daniel Wilkie, Mr Timothy Maxwell Mainprize, and Mr. Terry Cassidy was committed to trial charges as they were not doing their work honestly and stating the irregularities conducted by the company in their financial statement (Firth et al. 2016). Depicting the condition that might exists for a negligence action to be upheld: The overall negligence actions of HIH are mainly depicted as follows. Reduction in information independence: The limited knowledge depicted by HIH to its auditors and other regulatory authority could be helped as the negligence action against the company. Moreover, the auditors due to limited information were not able to comprehend the changing inherent risk of the company, which in turn increased its overall insolvency risk. Su (2015) stated that auditir5s in fear for the termination of their audit license mainly uses ethical principles in auditing companies financial statement. In addition, auditors and directors that knew about the misstatement conducted in the annual report could be upheld for negligence action in a court of law. Damaged governance practise of HIH: Moreover, the damaged corporate governance and followed in HIH insurance was the main reason behind the overall decline of the company. In addition, changes in risk exposure and commencement of high-risk insurance to clients were not depicted to the relative authority. Moreover, employees and internal auditors did not report to relevant authorities regarding the mismanagement and high-risk endeavours taken up by the company (Backof 2015). Ethics Depicting the reason that led to the appointment of prior members as external audit team for HIH: Due to the changing business perspective of HIH Insurance, it needed external auditors, which were the member of the company. In addition, inclusion of external auditors with prior member of the company might help in keeping its secret. Brown et al. (2013) argued that external auditors to increase their wealth accumulation mainly use unethical measures to hide the actual truth about the financial position of the company. In this context, Thomas (2012) mentioned that adequate permission needed by external auditors mainly helps in authenticating the overall auditors report and reduce manipulations conducted by the company. Moreover, the reasons for appointing prior members as auditors are as follows. The implementation of prior members as external auditors might help HIH insurance to reduce through checks of their financial report. Moreover, the external auditors might be able to understand the operations and requirements of different strategy due to their experience in the company. In addition, involvement and approval of previous directors mainly help investors to maintain trust for the company. Non-inclusion of different external auditors might help HIH to continue its unethical activities, which might help in retaining more profits for its members. Evaluating the advantages that might be provided by the firm depicting both auditing and consulting services: The auditing report and consulting services both provided by the auditing firm mainly helps in improving the overall operations of the company. In addition, the combined services might help the company to identify loopholes, and improve their overall operational capability. In this context, Hay et al. (2014) argued that combined auditing and consulting services might help companies to identify loopholes, which might help in portraying inflated balance sheet. Moreover, the advantages of using one firm for auditing and consulting are as follows. It could help the company identify errors in their audit process, which might help in reducing authenticity of their financial report. It could help in suggesting measures, which could be implemented by the company to reduce their overall expenditure. It could help in confining the internal secrets of the company and protect it from it competitors. The consultation and auditing firm are mainly helps in identifying errors and misstatements in the financials report, which could in turn hamper authenticity of the financial report. Helin and Babri (2015) stated that consultation firm mainly helps companies to reduce their tax by providing suggestions, which in turn increases their retained profits. Providing reasons for any ethical standard violation conducted by the company: After the effective evaluation of the HIH insurance company case it could be found that there were many ethical violations conducted by directors, external auditors and other members of the company. In addition, Arthur Anderson is mainly identified as the mainly culprit for taking advantage of the circumstance used by HIH Insurance. Moreover, around $1.7 million and $1.6 million was paid for auditing and consulting fees. Zadek et al. (2013) argued that ethical violation only takes place when the internal control of the company weakens, which leads to higher liquidity accumulation. The external auditors did not follows the auditing rules laid down by AASB and decreased. Moreover, the auditors did not complete their duties according to their rules laid down by AASB and helped HIH Insurance in inflating their financial report. The circumstance used by HIH Insurance to conduct external audit and change regulations laid down by prudential margin mainly states the ethical violation candied by its directors and auditors. Theses ethical violations were only conducted to increase their overall personal wealth (Pitt 2014). Depicting the recommendations that are provided by Ramsay report and CLERP 9, which might help in evaluating the impacts on auditing practise: Ramsay report and CLERP 9 mainly helped in identifying policies, which could be used in ethical financial reporting and governance. Moreover, the recommendation of th CLERP 9 and Ramsay report are as follows. To increase the overall wait time of the retied top management personal to join the external audit team from 2 to 4 years. To implement the auditing companies senior personnel involvement audit report of the company. To increase the rotation of members of external auditors to five years With the help of theses indentified policies the overall unethical measure could be reduced, which in turn might help in improving the overall authenticity of the financial report. Baker et al. (2014) stated that implementation of strict rules and regulation might help in igniting fear among unethical practitioners and increase authenticity of the financial report. On the other hand, William et al. (2016) criticises that due to greed, auditors mainly identifies different loopholes in new rules, which in turn reduces authenticity of the financial report. Conclusion: The overall assignment mainly helps in depicting the unethical measures conducted by HIH Insurance Company to inflate their financial statement. Moreover, the study also helps in identifying the insolvency and organisational structure risk identified as the main business risk for HIH Insurance Company. Moreover, the unidentified inherent risk mainly reduces the overall authenticity of the audit report prepared for HIH Insurance. Moreover, the novice effectively depicts legal liabilities that might be portrayed to Mr. Andersen for his unethical measures conducted in portraying the audit report. Moreover, with the help of Ramsay report and CLERP 9 ethical auditing could be conducted in business, which might help in authenticating their financial report. Reference: Arlen, J. and Carney, W.J., 2012. Vicarious liability for fraud on securities markets: Theory and evidence. Backof, A.G., 2015. The impact of audit evidence documentation on jurors' negligence verdicts and damage awards.The Accounting Review,90(6), pp.2177-2204. Baker, C.R., Bdard, J. and Prat dit Hauret, C., 2014. The regulation of statutory auditing: an institutional theory approach.Managerial Auditing Journal,29(5), pp.371-394. Brochet, F. and Srinivasan, S., 2014. Accountability of independent directors: Evidence from firms subject to securities litigation.Journal of Financial Economics,111(2), pp.430-449. Brown-Liburd, H.L., Cohen, J. and Trompeter, G., 2013. Effects of earnings forecasts and heightened professional skepticism on the outcomes of clientauditor negotiation.Journal of business ethics,116(2), pp.311-325. Faria, S.R., Alford, A., Garcia, S.C. and Fulkerson, W.J., 2013. An integrated assessment of business risk for pasture-based dairy farm systems intensification.Agricultural Systems,115, pp.10-20. Firth, M., Wong, S., Xin, Q. and Yick, H.Y., 2016. Regulatory sanctions on independent directors and their consequences to the director labor market: Evidence from China.Journal of Business Ethics,134(4), pp.693-708. Grant, K., Edgar, D., Sukumar, A. and Meyer, M., 2014. Risky business: Perceptions of e-business risk by UK small and medium sized enterprises (SMEs).International Journal of Information Management,34(2), pp.99-122. Hay, D., Knechel, W.R. and Willekens, M., 2014.The Routledge Companion to Auditing. Routledge. Helin, S. and Babri, M., 2015. Travelling with a code of ethics: a contextual study of a Swedish MNC auditing a Chinese supplier.Journal of Cleaner Production,107, pp.41-53. Mellichamp, D.A., 2013. New discounted cash flow method: estimating plant profitability at the conceptual design level while compensating for business risk/uncertainty.Computers Chemical Engineering,48, pp.251-263. Michelacci, C. and Schivardi, F., 2013. Does Idiosyncratic Business Risk Matter for Growth?.Journal of the European Economic Association,11(2), pp.343-368. Pitt, S.A., 2014. International standards for the professional practice of internal auditing. Sadgrove, K., 2016.The complete guide to business risk management. Routledge. Su, L., 2015. Do the auditors bear the consequences of corporate failures? The case of failed New Zealand finance companies. Thomas, S., 2012. Ethics and accounting education.Issues in Accounting Education,27(2), pp.399-418. William Jr, M., Glover, S. and Prawitt, D., 2016. Auditing and Assurance Services: A Systematic Approach.Auditing and Assurance Services: A Systematic Approach. Zadek, S., Evans, R. and Pruzan, P., 2013.Building corporate accountability: Emerging practice in social and ethical accounting and auditing. Routledge.