Depression article – page 2
                    

In 1980 Mendelwicz and Youdin reported results from a double-blind study comparing placebo, 300mg 5-HTP, and 5-HTP plus deprenyl. The 18 patients receiving deprenyl plus 5-HTP experienced depression relief significantly greater than those receiving placebo 5-HTP alone (34).

Quitkin and co-workers found deprenyl to be superior to placebo in a 6 week trial with 17 atypical depressive patients, and relatively free of-side effects.  9/10 positive deprenyl responders required a 30mg/day deprenyl dosage.  At doses above 20mg deprenyl is no longer a selective MAO-B inhibitor, but also begins to suppress MAO-A activity as well, as do standard MAOls.  Nonetheless, Quitkin noted: "There were no reported  hypertensive  ["cheese  effect") episodes.... L-deprenyl's relative freedom from other MAOI side effects may prove to be of major importance.... Several patients on a regimen of standard MAOls tolerated a six-week regimen of L-deprenyl quite well." (4)

J. Mann and colleagues reported positive antidepressant effect with deprenyl in a 44 patient double blind study in 1989.”   After six weeks and at higher doses (averaging about 30mg/day for the second three weeks), [deprenyl] was superior to placebo in antidepressant effect with a positive response rate of 50% vs. 13.6% and with a 41% reduction in the Hamilton depression Rating Scale mean score vs. 10% in the placebo-treated group.  No hypertensive crises were seen.  The rate of occurance of side effects with [deprenyl] was no greater than with placebo.... [deprenyl] is an effective antidepressant in a dose range where it is distinguished by the absence of many of the side effects typical of the nonselective MAO inhibitors." (33)

Based on a double blind, crossover study of placebo vs. 3 weeks of deprenyl, at 60mg/day dosage, T Sunderland and co-workers reported in1994 that "Selegiline [deprenyl] appears to be an effective antidepressant in older patients with treatment-resistant depression.... No serious side effects were noted during our study.... there was... an overall reduction in anxiety, and a decrease  in  self-reported irritability." (30)

All of the preceding studies were relatively short-term, typically 3 to 6 weeks.  Although only minimal side effects were noted, even at the unusually high deprenyl doses of 30-60 mg/day, the researchers did express concern about possible side effects at these higher doses with more typical long-term (months to years) antidepressant usage.  Two successful studies with treatment-resistant depressives have been done, however, they used very modest deprenyl doses of 5-10mg/day.  At this low dose, deprenyl remains a purely MAO-B inhibitor and is normally fairly side-effect free, even with long-term use.

In 1984 W. Birkmayer and colleagues reported their results from an open study of 155 serious, treatment-resistant depressives. "...102 unipolar [out-] patients... had depression for 3 to 15 years (range); only patients with at least five depressed phases were studied.  Usual antidepressant treatment was not successful before the start of a combined L-deprenyl and L-phenylalanine treatment. 

L-phenylalanine (250mg) and L-deprenyl (5-10mg) were given orally as a single morning dose for 28 to 96 days.... [53 inpatients] had severe unipolar depression for 3 to 15 years; again only patients with at least five episodes of depression were included.... Moreover, usual antidepressants were not effective in this group.       L-phenylalanine (250mg) and L-deprenyl (l0mg) were given intravenously as morning dose.  The duration of this combined treatment was between 14 and 28 days.... After 10 daily infusion we reduced to twice weekly and continued later with oral treatment. In a few patients this [oral] treatment was continued up to 24 months—without any loss of antidepressant effect." (35)

Sleeplessness, tension and anxiety were noted as adverse reactions - these are symptoms of dopamine/noradrenalin over-activation uncompensated for by counterbalancing serotonin activation - Tryptophan would have been appropriate to complement the deprenyl /phenylalanine treatment.   Birkmayer reports surprisingly excellent results based on modified Hamilton depression rating scale and global clinical impressions: 68.5% full remission and 21.5% moderate effect in the outpatients, with 69.5% full remission and 11% mild and moderate effects in the outpatients.

In 1991 H.C. Sabelli described his results from a small study with 10 treatment-resistant major depressives.  "treatment consisted of 5 mg deprenyl /day, 100 mg vitamin B6/day, and 1 gram phenylalanine a.m. and p.m., with gradual increase to 6 gm/day if needed. "Nine out of 10 patients experienced mood elevation within hours of phenylalanine administration, and 6 viewed their episodes of depression as terminated within 2 to 3 days.  Global Assessment Scale scores were significantly lowered after 3 days... and the improved scores were still observed 6 weeks later." (36)

Both the Birkmayer group and Sabelli relate the combined deprenyl/ phenylalanine treatment to enhancement of phenylethylamine (PEA) metabolism.  PEA and dopamine are the main substrates for MAO-B, which deprenyl inhibits.  Phenylethylamine is formed from phenylalanine with the help of a B6-activated enzyme.  PEA is a trace amine that may potentiate neuronal firing rates of noradrenalin/ dopamine neurons, especially when they're underactive (37).   Sabelli has shown that depressives have significantly lower blood and urine levels of PAA (the chief PEA break down product) than non-depressed controls.  He also notes that effective antidepressant treatment usually increases urinary PAA excretion, while antidepressant treatment that fails to successfully ameliorate depression also fails to increase urinary PAA excretion.   Low values of PAA excretion were observed in both retarded and agitated depressives (38).

In addition to being converted to PEA, phenylalanine can also be converted into the two "yang" neurotransmitters, noradrenalin and dopamine (39). Thus, a low dose deprenyl (5-10 mg), moderate dose I-phenylalanine (250 mg - 500 mg once or twice daily) and 50 mg  -100 mg dose of vitamin B6 regimen may serve to enhance mood, drive, and energy in the "apathetic-inhibited" type of depression, while tryptophan may serve to inhibit potential "overactivation" side effects of insomnia, anxiety, and irritability.  

NADH

J.G. and W. Birkmayer are pioneers in the use of NADH.  NADH is the active, reduced (electron-rich) coenzyme form of vitamin B3 -nicotinamide.  NAD/ NADH is the most plentiful coenzyme in the human brain.  NADH is the key in converting food into ATP bioenergy.  During normal oxidative metabolism, NADH is formed in both the glycolytic and citric acid (Krebs') cycles, and transferred to the electron transport chain, where each NADH can generate 3 ATPs.  NADH is the "linchpin" of oxidative energy metabolism (40).

NADH is also the indirect activator of tyrosine hydroxylase, the rate-limiting enzyme in the formation of dopamine and noradrenalin.  Tyrosine hydroxylase converts the amino acid tyrosine into L-dopa.  It can also convert phenylalanine into tyrosine.  Dopamine neurons convert L-dopa into dopamine, while noradrenalin neurons convert L-dopa first to dopamine, then into noradrenalin.

The  coenzyme that activates tyrosine hydroxylase is tetrahydrobiopterin (H4BP), which is produced from the B vitamin folic acid through an enzyme called H2 pteridine reductase (DHPR).  NADH activates DHPR, and thus is able to indirectly activate tyrosine hydroxylase and dopamine/ noradrenalin metabolism.  In a study of more than 400 Parkinson's patients, the Birkmayers demonstrated that NADH improved the symptoms of Parkinson's patients.  "Biochemical analysis showed that the improvement of clinical symptoms was paralleled by an increase of the dopamine metabolites HVA and VMA in the urine which provides indirect evidence that NADH is increasing the endogenous dopamine production.  Direct support for our hypothesis have been gained from tissue culture-experiments.  NADH added to the culture medium increased the production of dopamine in phaeochromocytoma cells up to 6 times.  Furthermore, tyrosine hydroxylase activity was stimulated by NADH to 175%." (41)

The Birkmayers and others had noticed that many Parkinson's patients suffer from depression, and the Birkmayers also observed their depressive symptoms disappear when successfully treating Parkinson's patients with NADH.  They therefore decided to use NADH in an open label (non-double blind) trial with 205 patients suffering depression with various symptoms.  NADH was given orally, intramuscularly, or intravenously, with doses of 5 to 12.5 mg.  Duration of therapy ranged from 5 to 310 days.  93% of the patients exhibited some degree of a beneficial clinical effect (41).  Gabriel Cousens, M.D. has also successfully used NADH to treat depression in his practice, based on Birkmayers' work.  He states that "About 85% of my clients with depression seem to benefit from taking NADH.... they may feel results from it within three weeks, sometimes sooner.  I'm very pleased with its antidepressant effect." (41A)  Because of its combined energy-enhancing role (the brain produces and uses 20% of the body's ATP energy total) and its ability to stimulate dopamine/ noradrenalin production, 5-10 mg NADH, taken once or twice daily on an empty stomach, may serve as a useful complement to the deprenyl/ phenylalanine program or may be simply used as a single therapy.

Gerovital: H3

Gerovital-H3 (GH3) (specially stabilized procaine) was developed in the 1940s by Ana Asian in Romania.  It is the original "anti-aging" drug.  In addition to its various physical benefits, such as improved joint mobility and pain relief, it was known by the 1960s that GH3 possessed antidepressant effect. By the 1970s at least part of the basis of GH3's antidepressant effect was known, GH3 was discovered to be a weak, reversible, fully competitive MAO inhibitor (42,43). The more toxic and dangerous MAOIs,such as ipromazid and phenelzine, are strong, irreversible, noncompetitive MAO inhibitors. It is this difference which makes them prone to the "cheese effect," i.e. potentially fatal hypertensive crises in patients who eat a tyramine-rich diet while taking them. GH3 researchers M.D. MacFarlane and H.Besbris noted that in contrast, "...the use of GH3 for the treatment of depression and for other manifestations of aging has not been associated with any significant adverse reactions and there are no restrictions regarding the type of food the GH3 patient can enjoy." (42) And contrary to the claims of critics that there is no difference between GH3 and ordinary procaine, MacFarlane noted that "when the ability of GH3 to inhibit MAO was compared with that of procaine hydrochloride (Novocain), it was found that GH3 produced a significantly greater inhibition of MAO than did procaine." (43) Zung and colleagues also remarked on the difference between GH3 and procaine: "Procaine when injected in the human body is rapidly hydrolized by cholinesterase into para-aminobenzoic acid (PABA) and diethylaminoethanol (DEAE).  In the case of procaine in the GH3 formula, metabolic studies show that the intact molecules of procaine can be found in blood or urine after six hours of administration of the drug." (44) Being a safe and effective (albeit mild) MAOI, GH3 can be expected to help raise dopamine, noradrenalin, and serotonin through inhibition of their neuronal MAO destruction, with consequent antidepressant effect.

Several studies in the 1970s found an antidepressant effect from GH3. Cohen and Ditman reported in 1974 that "Eighty five percent of 41 subjects reported some improvement from a series of 12 GH3 intramuscular injections.... Their response was prompt and dramatic, but mainly subjective. Most felt a greater sense of well-being and relaxation, slept better at night, and mainly obtained some relief from depression and the discomforts of chronic inflammatory or degenerative disease." (45)

W. Zung and co-workers reported a successful double-blind, placebo trial comparing GH3 with the tricyclic antidepressant imipramine in 1974. They concluded that "... the results of this study showed that using the clinical global impression and the Zung self depression scale, the change scores obtained from calculating pre-treatment to post-treatment differences showed GH3 to be superior to imipramine, since the GH3-placebo differences were  significantly  different,  while  the imipramine-placebo differences were not." (44)  The table listing side effects in the Zung study also shows that GH3 produced fewer side effects than both imipramine and placebo!

In 1984 paper pharmaceutical researcher Alfred Sapse expounded the disease-promoting power of chronic, excessive, stress-released cortisol. He gave a short list of substances that could oppose cortisol's negative actions. GH3 was one of five anti-cortisol agents Sapse recommended (46). And as Murphy and Wolkowitz point out, "Major depression is associated with a high incidence of cortisol hypersecretion.... this hypercortisolism is the most well-replicated biological abnormality in major depression...." (47) Thus, GH3's anti-cortisol action may also enhance its antidepressant effect.  Because of cortisol's power to induce liver tryptophan pyrrolase, the " tryptophan -destroying enzyme, GH3's ability to reduce cortisol may also provide antidepressant effect through enhancing brain tryptophan, and hence, brain serotonin status.  Thus, one tablet of GH3, taken once or twice daily (AM/PM) on an empty stomach may be a safe yet effective antidepressant, alone or in a combination with others in this article.

SAMe

S-adenosylmethione (SAMe) has recently become known to the public as an antidote for one of the most important heart disease risk factors, homocysteine.  A large number of studies have also shown SAMe to be an excellent and rapid-acting (often 3-7 days) antidepressant (48-53).  As SAMe research pioneer G.Stramentinoli has stated, "[SAMe) is an important physiologic compound that occurs in every living cell.... SAMe is probably second only to ATP [the basic energy molecule of life) in the variety of reactions in which it serves as a cofactor." (54) SAMe is the linchpin of all the body's transmethylation reactions. "...methyltransferase reactions …shift the 'active' methyl group of SAMe to a wide variety of methyl 'acceptor' molecules, including …biogenic amines [neurotransmitters), fatty acids, and phospholipids, proteins, nucleic acids, polysaccharides, and porphyrins.  In this role SAMe is the most important methyl group donor in mammalian tissue." (48)   SAMe's methyl group makes possible the production of neuronutrient acetyl l-carnitine, the stress hormone and neuro-transmitter adrenalin, and the neuronutrient and chief neuronal membrane fluidizer phosphatidyl choline (55).  SAMe has been shown to significantly increase cerebrospinal fluid levels of HVA and 5HIAA, the chief metabolites of dopamine and serotonin.  SAMe has been shown in antidepressant studies to possess mood-elevating and behaviorally arousing effects due to the SAMe-increased dopamine and serotonin activity, and due to a selective excitatory action on cortical neurons in the brain (48). 

In 1994 G.M.Bressa reported meta-analysis of 31 prior studies of SAMe's antidepressant effectsl  "The average [antidepressant] effect size of SAMe... derived from our meta-analysis of placebo-controlled trials-is therefore' slightly higher than that obtained by Greenberg et. al. ... for both standard tricyclic antidepressants and relatively   newer antidepressants.,.. Since SAMe is a naturally occurring compound with relatively few side effects, its antidepressant effect makes it a potentially important tool [for treatment of depression]" (53)

In general, side effects in SAMe studies are few and mild.  In some studies SAMe induced fewer or less serious side effects than placebo!  For example, in a double blind study with 734 people comparing SAMe with the painkiller naproxen and placebo, 10 people withdrew from the study due to side effects from SAMe, compared with 13 from placebo and 17 from naproxen side effects (56).  The most commonly reported side effects are gastrointestinal -primarily heartburn, nausea, and stomach ache (57).  However, the Gl effects seem to be mediated through the brain -they are not the result of direct Gl tract irritation.  SAMe actually inhibits and protects against Gl lining damage and irritation.  The other occasionally reported side effect of SAMe is mania or hypo-mania -i.e. excessive mood elevation and overstimulation.  This side effect is reported far more rarely than the Gl side effects.  SAMe-induced mania may on occasion be serious enough to warrant lithium treatment to end the mania.  Bipolar (manic) depressives should therefore use SAMe with caution.

SAMe has been given orally in doses ranging from 400 mg/day to 1600 mg/day.  SAMe is usually given in two or three doses daily, with 10 AM and 3 PM being a common time for twice daily administration (57).  Starting with low dose (200- 300 mg) once or twice daily and working up to higher doses if necessary is the best strategy.  Because SAMe tablets are (or should be) enteric-coated, they should not be cut in half to achieve a lower dose -the SAMe may then break down before absorption.

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REFERENCES

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