Analysis of SAMe as an Antidepressant

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