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Depression - 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 

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 Nivalin® (galantamine), also called ReminyI® in some countries.

Galantamine, the Unique Acetylcholinesterase

Galantamine has shown to have two methods of action, which make it special among the current range of acetylcholinesterase inhibitors.  
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

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. continued  

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