Ed.- This article looks at some of the new drug therapies that are showing promise in the treatment of depression and senile dementia. Specifically details are mentioned regarding the drugs; reboxetine, galantamine, moclobemide, tianeptine and picamilone.
In a recent extensive European survey, 17% of the adult population claimed they had suffered from depression in the last 6-months. So there may be good news for these millions of people, because over the last couple of few years there has been a explosion of new anti-depressive drugs. The most interesting aspect to this ‘new generation’ has been its approach. Previously, and almost uniquely the patient was subjected to some form of selective-serotonin reuptake inhibitor (SSRI), such as Prozac ®, Paxil ® or Zoloft ®. One could be forgiven for believing that the thinking was almost blinkered; The analogy that if one was depressed it was because brain serotonin levels were low, as a result- improving the level alleviates depression. SSRI’s do represent a significant improvement for the majority in the alleviation of depression by improving mood, and they and are a major advance over the use of slow acting tricyclic drugs, but to ‘blame’ serotonin levels for all forms of depression is far to simplistic. Other brain factors need to be considered, including the possibility of a ‘lack of brain energy,’ which may be the result of an imbalance of oxygen, blood or glucose levels, and of course the imbalance of other brain neurotransmitters. The individual’s interpretation of these varied brain imbalances may cause many patients to claim they are feeling depressed. As a result, many different kinds of drugs, some of which were originally designed for a completely different purpose, end up producing- what can only be described as an anti-depressant effect. This is especially true of stimulants, because often- the patient not only ends up feeling more alert but also reports an improvement in ‘well being.’ The relatively recent edition of the eugeroic drugs, adrafinil and modafinil (see my article in the IAS Anti-Aging Bulletin Volume 3 Issue 3, Winter 1997); with their unique action of selectively enhancing the activity of the neurotransmitter- noradrenaline were designed specifically as stimulants, but they lead not only to a stimulatory action but also the improvement of well being for most patients.
Whilst serotonin plays a vital role in mood, noradrenaline is essential to drive and motivation. Chronically depressed individuals typically have dysfunctional and atypical noradrenergic systems, particularly with regard to alpha-2 and beta-adrenoceptors. Reboxetine (trade name Edronax ®), is a recent anti-depressant development from the pharmaceutical company Pharmacia & UpJohn. It is a selective noradrenaline reuptake inhibitor (NARI) and it has shown itself to be effective in both the short term (4-8 weeks) and long-term (up to 12-months) for the treatment of depression. Apart from regulating energy, drive and motivation, the noradrenaline neurotransmitter is also involved in regulating the sleep-wake cycle, food intake, endocrine function and peripheral sympathetic function. Dr. Borson from Pharmacia & UpJohn stated ‘it is possible that movement, initiation speed and the stamina of individuals is conditioned in part by noradrenergic mechanisms.’
A long-term open label study was conducted with 139 people whose mean age was 74, two thirds of the participants were women. It was discovered that those patients who improved within a 6-week period maintained their gains over the year. Nearly 88% of the patients improved their depression and reboxetine was well tolerated. In fact improvements were noted to be better in severe depressive cases than those that could normally be achieved with SSRI’s.
A further extensive study by Pharmacia & UpJohn with 549 patients showed that reboxetine was as effective as Prozac ® within an 8-week period. Patients in the double-blind placebo controlled study taking reboxetine had a 19-point drop in depression scores compared to a 17-point drop for Prozac ®. Side effects with reboxetine were noted as dry-mouth, insomnia and constipation. The study was conducted at the Hospital Clinic in Barcelona, Spain by Dr. Juan Massana who stated; ‘these studies provide important information on the role that [noradrenaline] plays in depression and a possible treatment option for the many patients around the world who suffer from depression.’
There have been numerous other studies with up to 2000 patients taking part in double-blind placebo-controlled conditions. They all indicate that reboxetine is an effective anti-depressant with few and usually minor side effects. Reboxetine has proven to be effective in short term use and equivalent if not better than the ‘standard’ SSRI drug interventions.
The most noted side effects of reboxetine use have been dry mouth, insomnia, constipation, increased sweating, tachycardia and vertigo. Although it has proven to be safer than the SSRI’s, its use in patients with severe heart conditions is not advised. Furthermore, reboxetine should only be given under close supervision to subjects with a history of seizure disorders. As with nearly all anti-depressants switches from mania to hypomania have occurred, thus patients who suffer with chronic depression and suicidal tendencies require close supervision. At high dosages urinary difficulties in passing water have also been noted in a few rare cases, as such the maker recommends that persons with an enlarged prostate and glaucoma (increased pressure in the eyes) avoid use.
Ketoconazole has been shown to increase the concentration of reboxetine, therefore care may be advised if ingesting these two substances. MAO inhibitors are also not advised to be taken with reboxetine, as well as concomitant use of tricyclic, SSRI drugs and lithium; this is because potential reactions have not yet been studied in clinical trials. No tests have been conducted in pregnancy and therefore pregnant and lactating women must avoid use and as is normal with nearly all drugs, persons suffering from severe liver or kidney disorders should also avoid use, (to save repetition please apply these statements to all the drugs mentioned in this article). The maker also suggests the avoidance of certain types of anti-biotics including erythromycin, fluvoxamine and anti-fungals such as fluconazole, flecainide and cyclosporin. Interestingly in the makers drug-insert it also suggests avoidance of ergot derivative drugs (such as hydergine ®, bromocriptine or nicergoline), but within the time constraints for this article we couldn’t find the reason why.
Standard dosages have been 4mg to 8mg per day, up to 12mg (20mg per day were used for a few weeks in some trials), however as most side effects begin to appear at dosages in excess of 8mg per day there is probably little need to exceed 8mg per day.
Acetylcholine (ACh) is the neurotransmitter most affected in Alzheimer’s disease (AD); just like dopamine in Parkinson’s disease (PD); it undergoes an age related decline, and again like PD it is only when levels reach a severely low state that AD is actually diagnosed. In the United Kingdom, something like 20% of persons over the age of 65 are diagnosed with some severity of AD, this figure climbs to an alarming 50% for persons over the age of 80. Yet, while approximately $23,000 is spent per sufferer on AIDS, approximately $700 is spent per sufferer on Cancer, but only $15 is spent per AD sufferer on research each year (sic). So far, specific AD drugs have not been particularly effective and many have had quite toxic side effects (usually upon the liver). Whilst more natural products such as DMAE, Lecithin and Choline have been ingested in large quantities in order to try and improve ACh levels, they have not been that effective in AD; even when also consumed with Acetyl-L-Carnitine, (which has also been shown to be beneficial). Once again, to use the motor-trade analogy- if one waits until the engine is smoking, there’s little benefit to be had in changing the oil! The diagnosis of AD already indicates that major neuronal damage has taken place and the best that can be hoped for is a slowing down of the disease progression. Age related memory decline needs to be recognised and treated long before it becomes a senile dementia, if we are to live long and productive lives.
Some of the most recent and most promising new drug therapies for AD have focused on the enzyme acetylcholinesterase (AChE). This enzyme breaks down the neurotransmitter ACh and therefore its inhibition helps improve ACh availability, (these kind of AChE inhibitors are abbreviated to AChEI). A number of new AChEI’s have been developed in the last couple of years including Novartis’ Exelon( (rivastigmine tartrate) and Bayer’s metrifonate (an organo-phosphorous compound). But the most interesting of them all I believe is Janssen’s Nivalin( (galantamine), also called Reminyl ® in some countries.
Galantamine has been shown to have two methods of action, which make it special among the current range of AChEI’s. Firstly, it displays the deactivation of AChE thus improving ACh levels, but it also stimulates nicotinic receptors, which may release even more ACh. It is nicotinic stimulation that represents the new area for AD research and it is hoped that this will result in fewer amyloid plaques. These plaques have come to characterize AD, they are microscopic, spherical structures containing deposits of beta-amyloid peptide, dead and dying neurons and evidence of inflammation. Pooled data from galantamine trials indicate that improvements have been shown in cognitive and global scales commonly used to assess the progress of people with AD. Thus galantamine improved functional ability, memory and learning abilities. Whilst galantamine is specifically approved as an Alzheimer’s drug, it is perhaps not surprising to note that treatment with it usually responds in the patient feeling ‘better’ in themselves. In other words galantamine appears to also exhibit a mild anti-depressant effect.
Many countries are currently undergoing stage II and stage III clinical trials with galantamine, but Austria, Sweden and imminently the United Kingdom have already approved galantamine for use in Alzheimer’s disease. However, in a pivotal double-blind, placebo-controlled US study with 636 patients suffering from mild to moderate AD, 423 received galantamine twice a day for 6-months and 213 were given placebo. Sixty two percent were female and the mean age was 75. At the end of the period, the patients who received galantamine were on-average 3.8 points higher than the scores of individuals who took a placebo. The cognitive performance of those on placebo had on-average declined by 2 points, whilst those taking galantamine had improved on-average by 1.7
To date galantamine has not shown any major impact upon the liver in human trials. This is an important point because most AD treatments do affect the liver. One aspect of galantamine’s relative safety may be the fact that it is an extract of the Galanthus Nivalis L. plant, a type of snow- drop in the daffodil family. To date most side effects have been limited to increased respiratory function, dizziness, lowering of heart rate, increased sweat and saliva production, loss of appetite, nausea, sleep disturbance and headache. In an overdose case, a lowering of blood pressure and heart rate was seen.
Galantamine is contraindicated in myocardial infarction, bronchial asthma, epilepsy, low blood pressure, diabetes, ulcers, gangrene and Parkinsonism. The standard dosages have been 5mg taken twice a day, but under close supervision these dosages have been increased to 3-6 tablets (5mg each) daily taken in divided dosages.
Interestingly, the new drug tianeptine (brand name Stablon ®) is chemically related to amineptine (brand name Survector(). Amineptine was another unique drug (and we would have mentioned it in detail here this article, but for one reason- read on!). Amineptine was unique in that it was a dopamine reuptake inhibitor and was proving itself very worthy of being a useful anti-depressant, (as a quick review of any of the internet chat-groups will reveal). Unfortunately, for amineptine it appeared to help aid orgasm and as such was considered by the authorities to be a ‘drug of abuse and potentially addictive’ (sic). Many drugs that ‘interfere’ with dopamine have been shown to improve libido, particularly for men (deprenyl, L-dopa and GHB are good examples), but amineptine was perhaps more so? As a result, it is my understanding that the FDA pressured the foreign manufacturer to remove the drug from the marketplace. I know a lot of patients who miss its anti-depressive effect, but this is hardly the first time such actions have been taken (minaprine and fipexide are another two unique drugs sorely missed), and I am sure it won’t be the last time either.
So tianeptine is chemically related to amineptine, but it does not present itself as a dopamine reuptake inhibitor. Instead it displays another totally unique action, tianeptine is a serotonin reuptake accelerator and works exactly opposite to the SSRI’s. Whereas SSRI’s try to keep as much serotonin as possible in circulation, tianeptine takes as much of it as possible out of circulation! Yet tianeptine still works, it actually stimulates the uptake of serotonin and reduces the hypothalamic-pituitary-adrenal response to stress.
In trials, tianeptine has been shown to be well tolerated in the short term (3-months) and the long term (1-year). In particular it has been noted that tianeptine is effective in depressed patients who also suffer from anxiety, and also that sleep is improved. One study suggested that tianeptine can be placed in a middle position in the bipolar classification, between the sedative and stimulant antidepressants. Tianeptine has been compared to other ‘standard’ anti-depressants such as fluoxetine (Prozac ®), the results of the studies suggest that tianeptine exhibits good efficacy and safety. Tianeptine is a new and novel serotonin drug, its antidepressant and anxiolytic properties and its action on somatic complaints make the drug particularly suitable for the treatment of the entire range of depressive symptomatology.
Possible side effects have to date been reported as dry mouth, anorexia, nausea, flatulence and gastralgia. In rare cases were the drug has been administered in the late evening, insomnia and nightmares have been reported. Further rare side-effects include dizziness, faintness and repiratory discomfort, however taken as a whole the side effects with tianeptine are a very short list compared to many other of the standard anti-depressants. Tianeptine should not be taken with MAO inhibitors, and the maker suggests an interval of at least 15-days between a MAOI and tianeptine use. Although not clearly stated, use with other anti-depressants, especially those that alter serotonin levels should only be undertaken under the close supervision of your physician. Dosages have been 12.5mg two or three times a day.
A lot of focus has been placed over the years on monoamine oxidase (MAO). MAO is an enzyme that helps break down neurotransmitters, as such inhibiting MAO leads to an improvement in the availability of the brain neurotransmitters (these inhibitors are abbreviated to MAOI). At first, the early drug developments were irreversible MAOIs, these exhibited the so-called cheese effect, whereby the ingestion of certain foodstuffs containing tyramine (such as cheese and red wine etc) could cause a life-threatening situation. Gerovital-H3 ® was noted as being one of the first and most effective mild reversible MAOIs to appear in the marketplace, and is undoubtedly one of the reasons why it has an anti-depressive effect and remains one of the most popular anti-aging medicines even today. (Ed.- there is a separate article in this issue about Gerovital-H3 ® and depression written by Mircea Dumitru MD). So later came the development of safer reversible MAOI drugs. MAO can be split into two factions, MAO-A and MAO-B, the -A suffix being the most abundant and potent of the two. Currently, all drugs when inhibiting MAO manage to inhibit both the -A and the -B; but there are two exceptions, one is deprenyl (selegiline) which only inhibits -B (Ed., Professor Joseph Knoll spoke at the June 2000 Monte Carlo Antiaging Conference ™ and stated that he now believes that deprenyl’s action has much less to do with MAOI-B than he first believed, a video is available if interested), and the other is moclobemide.
Moclobemide (brand name Manerix ®) developed by Roche is a selective, short acting and reversible MAO-A inhibitor designed as an anti-depressant. It has been shown to increase concentrations of serotonin and noradrenaline in the brain. As a result of its action, it interaction with dietary amines causes considerably less increase in blood pressure than with the classic MAO inhibitors.
Studies have shown that moclobemide is as effective as the tricyclics and much better tolerated and is considered to be comparable to the SSRI’s in both efficacy and tolerability. One study compared a dose of moclobemide of 450mg and fluoxetine (Prozac ®) at 20mg daily, two groups of approximately 60-patients each were selected for either an 8-week trial or a 1-year trial. Within 8-weeks the efficacy data showed there was little difference between the effectiveness of either moclobemide or fluoxetine with anti-depressive benefit for 63% and 70% respectively. At the 1-year stage there were no severe side effects in either group and the study concluded that in both groups patients were much or very much improved. The data from the study also pointed out that moclobemide produced far fewer side-effects than fluoxetine.
There is little clinical evidence to support the use of other anti-depressants with moclobemide, however one Australian study suggested that ‘[moclobemide] can have significant interactions with both selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants (TCAs), even in therapeutic doses.’ Therefore combination with any anti-depressants should not be undertaken unless under the close supervision of your physician. The makers insert also states that moclobemide should not be used if you suffer from a tumor of the adrenal glands, and caution is also advised if you suffer from a thyroid condition. Under normal conditions, with the ‘standard’ dosages of 300mg to 450mg daily (dosages have been as high as 600mg to 900mg daily but as usual more side effects present themselves at higher doses), side effects have been noted as sleep disturbances, dizziness, headache and confusion. But remember that studies have shown moclobemide to have fewer side effects than standard SSRI drugs and may be more effective in cases of mild to moderate depression. Dosages are normally 150mg twice or three times a day.
That brings me around to the last relatively new drug that is showing promise in the battle against depression. To be fair this particular drug should have an article dedicated to itself, and if you contact IAS and request it, who knows maybe one will appear in a future issue of the IAS Anti-Aging Bulletin! (Ed., Robert are you trying to get more work?) The drug in question is Picamilone (sometimes also spelt Pikamilone with or without the e on the end). Officially it is an anti-anxiety drug, but is also possesses stimulatory properties and anti-depression qualities too. Often I believe that anxiety is the cause of depression and vice-versa and I refer back to my original comment in the early part of this article, where I stated; ‘The individual’s interpretation of these varied brain imbalances may cause many patients to claim they are feeling depressed.’ In other words, we are never taught how to interrupt different feelings, and so very often the words that the doctor hears are simply ‘I’m depressed.’
Picamilone is a Russian development, it is in essence the bonding of niacin (vitamin B3) to GABA. This combination acts very differently and uniquely and can’t be compared to just taking both niacin and GABA together as individual supplements. We know that niacin is very effective in crossing the blood-brain barrier and has been shown to enhance cognitive function by protecting the neurons against the effects of diminished blood flow. GABA on the other hand has a placating action, possibly helping to stabilise other neurotransmitters and have a calming affect.
Picamilone is a very effective vasodilator (it improves brain blood flow), in fact Russian experiments suggest that picamilone is better than hydergine ® and even better than vinpocetine in this regard. I would consider vinpocetine to be the current industry leader in regard to its vasodilatation action, so for picamilone to be considered better is praise indeed. (Ed., Remember the excellent article about vinpocetine by James South MA in the IAS Anti-Aging Bulletin Volume 3 Issue 5, Summer 1998). It appears that the synergism between niacin and GABA is very strong indeed. For whilst vasodilatation is occurring, more likely the result of the niacin (xanthinol nicotinate is considered to be the most potent form of niacin) it is also displaying a mild tranquillising effect, which helps prevent the negative effects of emotional stress. This second trait is the likely affect of GABA, as it is with the basis of the diazepam tranquillising drugs (such as Valium ®) which inhibits the reuptake of GABA, the presence of GABA appears to have a calming affect upon us. But what makes picamilone unique is that whilst it counteracts stress and anxiety, it doesn’t have a sedative action, in fact quite the reverse it can have a mild stimulatory action. Picamilone may be the first anti-anxiety drug that literally doesn’t make you drowsy! Again Russian studies (picamilone has been available in the CIS countries since 1989), have compared picamilone with other psycho-stimulant drugs including Nootropil ® (piracetam), phenazepam, diazepam, vinpocetine, xanthinol nicotinate (Complamin ®) and papaverine. It was noted that the stimulant properties of picamilone were greater than that of piracetam, after taking picamilone the patients felt better and giddiness and tremor disappeared. Further benefits of picamilone over the ‘classic’ tranquillising drugs are that it does not display any signs of inducing muscle relaxation, lethargy or drowsiness. Picamilone has a number of positive benefits for the patient, it can reduce anxiety, lower stress and yet at the same time display a non-sleepy action or indeed even a stimulatory property. As such, many patients exclaim that they have a ‘good feeling’ whilst using the supplement.
The good news is that in over 10-years of use in the former Russian states picamilone can be considered to be a very safe drug. It has not been shown to produce any allergenic, teratogenic, embryotoxic or carcinogenic effects. Most side effects have been noted as headache, dizziness and nausea. It has been stated that at higher dosages picamilone can lower blood pressure, and whilst this may be advantageous in some cases those persons with already low blood pressure should be monitored. Due to its potent properties it is advisable not to use any other vasodilating agents whilst using picamilone unless under the close supervision of a physician. Apart from the known listed drugs this list may also want to include vinpocetine, ginkgo biloba, niacin derivatives (such as xanthinol nicotinate) and the ergot preparations such as bromocriptine, hydergine ® and nicergoline. If taking high dosages of picamilone other nootropic agents such as piracetam and its analogues may also need to be listed.
The effects of picamilone are fast acting, often within an hour and the half life usually ensures that these effects continue for a period of approximately 6-hours. Accordingly dosages have been applied twice or three times daily, but late evening use should be avoided otherwise insomnia may ensue. Dosages for anti-anxiety are approximately 50mg 2 or 3 times daily, if a stimulatory property is also required this should probably have to be increased to more like 100mg 2 or 3 times daily.
Unfortunately, there hasn’t been enough time or space to elaborate on the many properties and uses of picamilone. To list a few of the known clinical results, picamilone has shown promise in memory, mood, anxiety, stress, motor and speech disturbances, sleep, irritability, alcohol withdrawal and visual acuity.
I hope that what I have managed to achieve in this small article is an idea of the new directions in which anti-depression treatments are going with the latest commercially available brain drugs. The main hope is that at long last the pharmacological treatment for depression is being looked at on a multi-level, encompassing new and novel approaches. The main draw-back to the new therapies is the lack of knowledge in how to use many of these different products in unison, in order to take advantage of any potential synergy. More often than not any combination is shied away from by the manufacturer because of concerns of liability and the onus falls onto the physician to use his or her knowledge and skill to estimate the best solutions. Hopefully, in the not-to-distant future we shall see the instigation of good tests that may enable the physician to determine the precise cause of the depression and treat it accordingly and not to rely solely upon what’s written in the Physician’s Desk Reference.
References
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