- New Drug Treatments
 by Robert Mason Ph.D.                     

In a recent extensive European survey, 17% of the adult population claimed they had suffered from depression in the last 6-months. But there may be good news for these millions of people, because over the last couple of 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, patients were given a selective-serotonin reuptake inhibitor (SSRI) such as Prozac®, Paxil®, or Zoloft®.  The thinking was that depression occurred because brain serotonin levels were low.  Therefore, by raising serotonin levels, depression could be alleviated.  SSRI's do represent a significant improvement for the majority of people suffering depression and they are a major advance over the use of slow-acting tricyclic drugs.  But to attribute low serotonin levels for all forms of depression is far too simplistic.  Other 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.  Also to be considered is the imbalance of brain neurotransmitters other than serotonin.  The individual's interpretation of these varied brain imbalances may cause many patients to claim that they feel depressed.

Several different kinds of drugs, some of which were originally designed for a completely different purpose, have been found to produce an anti-depressant effect.  This is especially true of stimulants which often make the patient feel more alert but often also produce an improvement in feelings of "well-being."  The relatively recent edition of the eugeroic drugs, adrafinil and modafinil; 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.

The Noradrenaline Factor 

While 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.  Edronax® is a selective noradrenaline reuptake inhibitor (NARD 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."

Reboxetine- Clinical Trials             to order 

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 17point 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 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.

Reboxetine- Dosages, Contraindications and Side Effects

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 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 patients 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 have also been noted in a few rare cases.  As such the manufacturer recommends that persons with an enlarged prostate or glaucoma (increased pressure in the eyes) avoid use.

The anti-fungal Ketoconazole has been shown to increase the concentration of reboxetine.  Reboxetine should not be taken with tricyclic antidepressants, MAO inhibitors, SSRI’s, and lithium because potential reactions have not yet been studied in clinical trials.  No tests have been conducted in pregnancy; therefore pregnant and lactating women should avoid reboxetine.  Persons suffering from severe liver or kidney disorders should also avoid reboxetine, (these cautions apply to all of the drugs mentioned in this article).

The maker also suggests the avoidance of certain types of antibiotics including erythromycin, fluvoxamine and anti-fungals such as fluconazole, flecainide and cyclosporin.  The manufacturer’s drug insert also suggests avoidance of ergot derivative drugs (such as Hydergine, bromocriptine, and nicergoline).

Standard dosages have been 4mg to 8mg per day, up to 12mg (20mg per day were used for a few weeks in some trials).  There is probably little need to exceed 8mg per day as most side effects begin to appear at dosages in excess of 8mg per day.

The Acetylcholine Factor

Acetylcholine levels decline as we age and acetylcholine is the neurotransmitter most affected in Alzheimer's disease.  Just as in Parkinson's disease where there is reduced dopamine, it is only when acetylcholine levels reach a severely low state that Alzheimer's is actually diagnosed.  In the United Kingdom, an estimated 20% of people over the age of 65 are diagnosed with some degree of Alzheimer's.  This figure climbs to an alarming 50% for people over the age of 80.  Yet while $23,000 is spent on AIDS research each year per AIDS patient, less than $700 is spent per cancer patient, and only $15 is spent on research per Alzheimer's patient.  So far, specific Alzheimer's drugs have not been particularly effective and many have had quite toxic side effects (usually upon the liver).  While natural products like DMAE, Lecithin, and Choline have been taken in to raise Acetylcholine levels in Alzheimer's patients, they have not been very effective even when taken with Acetyl L-Carnitine, (which has shown to be beneficial).  To use an analogy if one waits until the engine is smoking before changing the oil, there's little benefit to be gained from the oil change.  The diagnosis of Alzheimer's 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 recognized and treated 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 Alzheimer's have focused on the enzyme acetylcholinesterase (AChE).  This enzyme breaks down the neurotransmitter Acetylcholine and therefore its inhibition helps improve Acetylcholine availability, (these kinds of ACh5 inhibitors are abbreviated AchEl).  A number of new AChB's have been developed in the last couple of years including Novartis' Exelon® (rivastigmine tartrate) and Bayer's metrifonate.  But the most interesting of them all, I believe, is Janssen's Reminyl® (galantamine).

Galantamine, the Unique AchEl

Galantamine has shown to have two methods of action, which make it special among the current range of AChEl's.  
1). It delays the deactivation of the enzyme acetylcholinesterase thus improving Acetylcholine levels.
2). It also stimulates nicotinic receptors, which may release even more Acetylcholine.  
It is nicotinic stimulation that represents the new area for AIzheimer's research and it is hoped that this will result in fewer amyloid plaques which have come to characterize Alzheimer's.  They are microscopic, spherical structures containing deposits of beta-amyloid peptide, dead and dying neurons and evidence of inflammation.  Data from galantamine trials indicate that improvements have been shown in cognitive and global scales commonly used to assess the progress of people with Alzheimer's. Thus galantamine improved functional ability, memory, and learning ability.  While galantamine is specifically approved as an AIzheimer's drug, it also appears to produce a mild anti-depressant effect.

Galantamine, the Clinical Trials          to order 

Galantamine has been approved in Austria and Sweden for Alzheimer's disease and it is currently undergoing stage II and stage III clinical trials in several other countries.  In a pivotal US study with 636 Alzheimer's patients, the galantamine group recorded an improvement of 1.7 points while the control group performance declined by 2 points.

Galantamine-Dosages, Contraindications and Side Effects

To date galantamine has not shown any impact upon liver function in human trials.  This is a significant point because most Alzheimer's treatments negatively affect the liver.  One aspect of galantamine's relative safety may be the fact that it is an extract of the Galanthus Nivalis 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 dosage has been 5mg twice daily but dosages as high as 6 tablets (5mg each) daily have been used. 

Tianeptine, the Novel Serotonin Activator

Interestingly, the new drug tianeptine (brand name Stablon®) is chemically related to amineptine (brand name Survector®).  Amineptine was a drug unique in that it was a dopamine reuptake inhibitor and was proving very popular as an antidepressant, (as a quick review of any of the internet chat-groups will reveal).  Unfortunately, it appeared that amineptine helped aid orgasm and as such was considered by the authorities to be a "drug of abuse and  potentially addictive".  Many drugs that "interfere" with dopamine have been shown to improve libido, particularly for men (for example deprenyl, L-dopa, and GHB).  But perhaps amineptine was even stronger.  As a result, it is my understanding that the FDA pressured the foreign manufacturer to remove the drug from the market.  But this is hardly the first time such actions have been taken (minaprine and fipexide for example), and I am sure it won't be the last time.

While tianeptine is chemically related to amineptine, it is not 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 increase serotonin, tianeptine takes serotonin out of circulation.  Yet tianeptine still works.  It stimulates the uptake of serotonin and reduces the hypothalamic-pituitary-adrenal response to stress.

Tianeptine- the Clinical Trials

In trials, tianeptine has shown to be well tolerated in the short term (3-months) and the tong term (1-year).  In particular it has been noted that tianeptine is effective in depressed patients who also suffer from anxiety and disturbed sleep.  One study suggested that tianeptine can be placed in a middle position in the bipolar classification, between the sedative and stimulant antidepressants. When compared in clinical studies to other antidepressants such as fluoxetine (Prozac®), 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 symptomology.

Tianeptine- Dosages, Contraindications and Side Effects

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 respiratory discomfort, however taken as a whole the side effects with tianeptine are few 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 MAOl).  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 aged cheese and red wine) could cause a life-threatening situation.  Gerovital-H3 was noted as being one of the first and most effective mild reversible MAOls 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 antiaging medicines today.  Later came the development of safer reversible MAOI drugs.  MAO can be divided into few categories, MAO-A and MAO-B, the-A form being the more abundant and potent of the two.  All MAO inhibitors inhibit both the MAO-A and the MAO-B except deprenyl (selegiline) and moclobemide which only inhibit MAO-B.

Moclobemide-The Unique MAO-A Inhibitor

Moclobemide (trade 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 brain levels of serotonin and noradrenaline.  Moclobemide’s interaction with dietary amines causes considerably less increase in blood pressure than with other MAO inhibitors.

Moclobemide-the Clinical Trials

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 450mg dose of moclobemide and fluoxetine (Prozac®) at 20mg daily.  Two groups of approximately 60-patients 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 (Prozac®) 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 of patients were much or very much improved. The data from the study also showed that moclobemide produced far fewer side-effects than fluoxetine.

Moclobemide- Dosages, Side Effects and Contraindications

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 (SSRI's) 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 also advised if you suffer from a thyroid condition.  Under normal conditions, with the "standard" dosages of 300mg to 450mg daily 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.

Other Novel Approaches

That brings us to the last relatively new drug that is showing promise in the battle against depression. The drug is Picamilon (sometimes also spelled 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. I believe that often times, 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."

Picamilon-The Russian Connection        to order

Picamilon is a Russian development, it is in essence the bonding of niacin (vitamin B3) to the amino acid GABA. This combination acts very differently and uniquely and can't be compared to taking niacin and GABA together as individual supplements.

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 calming action and possibly helps to stabilize other neurotransmitters.

Picamilon- Anti-Anxiety, Anti-Depression & Stimulation, All in One?

Picamilon is a very effective vasodilator (it improves brain blood flow).  In fact Russian research suggests that Picamilon is a better vasodilator than both Hydergine and vinpocetine.  I would consider vinpocetine to be the current industry leader in regard to its vasodilatation action, so for Picamilon to be considered better is indeed noteworthy.

It appears that the synergism between niacin and GABA is very strong.   For while Picamilon produces vasodilatation (likely the action of niacin), it also produces a mild tranquilizing effect which helps prevent the negative effects of emotional stress.  The tranquilizing effect is likely produced by GABA, as it is the basis of the diazepam tranquilizing drugs (such as Valium®) which inhibit the reuptake of GABA.

But what makes Picamilon unique is that while it counteracts stress and anxiety, it doesn't have a sedative action.  In fact quite the opposite; it can have a mild stimulatory action.  Picamilon may be the first anti-anxiety drug that doesn't make-you drowsy.  Russian studies going back to 1989 have compared Picamilon with other psycho-stimulant drugs including piracetam (Nootropil®), phenazepam, diazepam, vinpocetine, xanthinol nicotinate, and papaverine.  It was noted that the stimulant properties of Picamilon were greater than that of piracetam.  After taking Picamilon the patients felt better and giddiness and tremor disappeared.  Further benefits of Picamilon over the traditional tranquilizing drugs are that it does not display any signs of inducing muscle relaxation, lethargy, or drowsiness.

Picamilon has a number of positive benefits.  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" while using the Picamilon.

Picamilon-Dosages, Side Effects and Contraindications

With over 10 years of use in the former Russian states, Picamilon is considered to be very safe.  It has not been shown to produce any altergenic, teratogenic, embryotoxic, or carcinogenic effects. Most side effects have been noted as headache, dizziness and nausea, ft has been stated that at higher dosages Picamilon can lower blood pressure, and while this may be advantageous in some cases those persons with low blood pressure should be monitored.  Due to its potent properties it is advisable not to use any other vasodilating agents while using Picamilon unless under the 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. 

The effects of Picamilon are fast acting, often within an hour the effects continue for a period of approximately 6 hours.

Accordingly, dosages have been applied two or three times daily, but late evening use should be avoided otherwise insomnia may result.  Dosages for anti-anxiety are approximately 50mg 2 or 3 times daily.  If a stimulatory effect is required, the dosage should be increased.

Picamilon- The Conclusion

Unfortunately, there hasn't been enough time or space to elaborate on the many properties and uses of Picamilon. To list a few of the known clinical results, Picamilon has shown promise in memory, mood, anxiety, stress, motor and speech disturbances, sleep, irritability, alcohol withdrawal, and visual acuity,

The Conclusion of the New Generation of Brain Drugs and Anti-Depressants 

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 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.  This leaves it in the hands of the physician to use his or her knowledge and skill.

Hopefully, in the not-so-distant future we shall see the development of tests that will 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.

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