- New Drug Treatments
by Robert Mason Ph.D.
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.
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.
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.
(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
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.
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."
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.
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.
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).
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).
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
The Acetylcholine Factor
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
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.
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).
the Unique AchEl
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.
the Clinical Trials
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
Contraindications and Side Effects
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.
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.
the Novel Serotonin Activator
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
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.
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.
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.
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.
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.
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.
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
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
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.
Dosages, Side Effects and Contraindications
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.
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
Picamilon is a Russian
development, it is in essence the bonding of niacin (vitamin B3) to the amino
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.
Anti-Anxiety, Anti-Depression & Stimulation, All in One?
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
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.
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
a mild stimulatory action. Picamilon may be the first anti-anxiety drug that doesn't make-you
drowsy. Russian studies going back
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
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.
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.
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.
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.
effects of Picamilon are fast acting, often within an hour the effects continue for a period of approximately 6
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.
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,
Conclusion of the New Generation of Brain Drugs and Anti-Depressants
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.
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.
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