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Beating depression
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Beating Depression, with Alternative Anti-aging Therapies
by James South MA
Depression is one of the most widespread illnesses in the
Western world, yet it is also one of the most misunderstood
and under treated health problems. Approximately 10-14 million
people are medically depressed in the U.S. in any given year,
yet only one third of depressives receive treatment (1). "Depression
is just as socially debilitating as coronary artery disease,
and more debilitating than diabetes mellitus or arthritis.
Up to 15% of severely ill depressed patients will ultimately
commit suicide" (1).
Untreated depression carries a huge list of costs: up to
30,000 suicides/year in the U.S., fatal accidents due to impaired
concentration and attention; alcohol and drug abuse; lost
jobs and productivity; job related injuries; and dysfunctional
families, to name just a few (1).
Psychiatrists normally define major depression as including
5 or more of the following 9 symptoms, lasting two weeks or
more (1):
1. Depressed mood 2. Diminished interest or pleasure in normal
daily activities 3. Significant weight loss without dieting,
or rapid weight gain; loss or excess of appetite 4. Insomnia
or hypersomnia 5. Psychomotor retardation or agitation 6.
Fatigue, loss of energy 7. Feelings of worthlessness or inappropriate
guilt 8. Diminished ability to think or concentrate, indecisiveness
9. Recurrent thoughts of death, recurrent suicidal ideation,
specific suicide plan or attempt
Public misunderstanding of depression is widespread. "A
recent survey of the general population revealed that 71%
thought that mental illnesses were due to emotional weakness;
65% thought it was caused by bad parenting; 45% thought it
was the victim's fault and they could will it away; 43% thought
mental illness was incurable; 33% thought it was the consequence
of sinful behavior; and only 10% thought it had a biological
basis or involved the brain." (1) During the past 50
years neuroscience, psychiatry and pharmacology have demonstrated
unequivocally that compromised brain function plays a key
role in depression, and that proper therapeutic manipulation
of brain chemistry can frequently alleviate or "cure"
depression, without resorting to years of psychoanalysis.
Researcher Paul Willner, in his massive work Depression: A
Psychobiological Synthesis, summarizes the chief neurochemical
difficulties in depression: "The major changes in neurotransmission
associated with severe depression are (1) a reduced level
of DA [dopamine] function, related to psychomotor retardation,
and reflecting a reduced level of incentive motivation; (2)
a retarded level of 5-HT [serotonin] function, related to
psychomotor agitation, and reflecting an inability to relax;
(3) a reduced level of NA [noradrenalin] function, ... reflecting
inability to maintain effort; and (4) cholinergic [acetylcholine]
hyperactivity, ... reflecting a high level of stress. Antidepressants
reverse these changes, primarily by actions on NA and 5-HT
neurons." (2)
5-HT, DA, and NA are each made from a single amino acid -
5-HT from tryptophan, and DA/NA from either phenylalanine
or tyrosine. Hence they are called "monoamine" (MA)
neurotransmitters. Since the 1950's various types of drugs
have been used by doctors and psychiatrists to enhance brain
MA neurotransmitter function. The first medical antidepressant
(since retired due to toxic side effects) was iproniazid,
a monoamine oxidase inhibitor (MAOI). MAO enzymes are present
inside neurons, as well as other cells including the liver,
where they serve to break down MA neurotransmitters. Some
MAs are broken down by MAOs as soon as they're formed, even
before they can be released into the synaptic gap to "fire"
the next neuron. MAs which are discharged into the synaptic
gap are sooner or later re-taken up by the neuron that secreted
them. They are then either repackaged for re-use, or destroyed
by MAO enzymes. MAOI drugs thus act to increase the synaptic
availability of MAs by preventing their breakdown by MAO enzymes.
This may increase the intraneuronal levels of 5-HT and other
MAs by 300% (3). However, MAOIs can also increase the neuronal
and blood levels of another substance called "tyramine",
found in many common foods, and induce severe, even fatal,
high blood pressure reactions unless a rigid low-tyramine
diet is followed, as well other side effects, such as postural
hypotension, sexual dysfunction, heart problems and insomnia
(4). The next generation of drugs believed to enhance brain
5-HT and NA became available in the 1960s: the tricyclic antidepressants
(TCA), such as imipramine and amitryptilene. TCAs seem to
attach to and inhibit the neuronal re-uptake sites for 5-HT
and NA, preventing the return of the MAs to the neuron which
secreted them. This enhances MA action in two ways. Since
most MAs returned to their source neuron are broken down by
MAO enzymes, TCAs slow MA breakdown. TCAs also cause more
5-HT and NA to remain in the synaptic gap, thereby increasing
5-HT/NA neuro-transmission. However, TCAs also affect other
receptors on neurons which respond to acetylcholine, histamine,
and DA. TCAs thus suffer from a wide range of unpleasant side
effects, ranging from drowsiness, confusion and blurred vision
to hypotension and movement disorders (5). TCAs are now considered
"antiquated" by, most psychiatrists, yet many general
practice physicians still favor them.
The 1980s spawned the current favorites among antidepressant
drugs: the serotonin-specific reuptake inhibitors (SSRIs).
The first and most famous of these is fluoxetine (Prozac®).
Other SSRIs such as paroxetine (Paxil®), sertaline (Zoloft®)
and fluroxamine (Luvox®) are also now in vogue in America
and Europe. These drugs are used to treat eating disorders
and obsessive-compulsive disorders as well as depression.
They have put 5-HT (serotonin) "on the map" with
the general public as "the mood molecule." 5-HT
drugs were the cover story for Time magazine on September
29, 1997. The Time article noted: "So far, the [drug]
tools used to manipulate serotonin in the brain are more like
machetes than scalpels-crudely effective but capable of doing
plenty of collateral damage." Robert Julien, in his text
A Primer of Drug Action, notes that side effects of Prozac®
may include nervousness, anxiety, sexual dysfunction, insomnia,
nausea, loss of appetite, motor restlessness and muscle rigidity
(5). Psychiatrist Peter Breggin, in Talking Back To Prozac,
also provides evidence that Prozac® may actually damage
serotonergic nerves and create an addictive-necessity for
long-term Prozac® use, as well as incline some users to
sudden suicide with no prior warning (6).
Thus, given their side effect profiles, their xenobiotic
nature (they're molecules foreign to normal brain metabolism),
and their need for rigid special diets and/or careful medical
monitoring to insure safe usage, the MAOIs, TCAs and SSRIs
cannot reasonably be considered the ideal remedies for depression.
Fortunately, neuroscience over the past 40 years has also
uncovered some simpler and more natural remedies for depression,
as well as several "life-extension" drugs with far
more safe and gentle antidepressant effect.
TRYPTOPHAN AND 5HTP - NATURE'S ANSWER TO PROZAC®
Studies with humans and animals over the past 35 years have
shown that 5-HT (serotonin) nerve circuits promote feelings
of well-being, calm, personal security, relaxation, confidence
and concentration (7). 5-HT neural circuits also help counterbalance
the tendency of overactive (e.g. due to genetics, stress or
drugs) DA and NA circuits to encourage over arousal, fear,
anger, tension, aggression and violence, obsessive compulsive
actions, anxiety and sleep disturbance (7). A deficiency of
5-HT nerve action has been shown to manifest as a broad array
of emotional and behavioral problems, ranging from depression,
premenstrual syndrome, anxiety, alcoholism and overeating
to compulsive gambling, fire-starting, thrill-seeking through
violence and suicide.
There is rarely a problem with the structure or "wiring"
of the brain's 5-HT circuits. Rather the problem is caused
by a chronic deficit of 5-HT in the nerves which use it as
their neurotransmitter. It is no coincidence that the most
popular psychiatric drugs in history are the SSRIs, and the
common thread connecting MAOIs, TCAs, and SSRIs is their 5-HT
neural effects. 5-HT is the "Achilles heel" of the
human brain. Yet no neuron suffered a literal deficiency of
these xenobiotic drug molecules. 5-HT neurons can, and frequently
do, however, suffer a deficit of the raw material from which
neurons normally produce 5-HT: the essential amino acid tryptophan
(Tryp).
In any normal diet, animal or vegetarian protein based,
Tryp is the least plentiful of the 22 dietary amino acids.
A typical diet provides only 0.75 to 1.5 grams Tryp/day, yet
there is much competition in the body for this scarce amino.
It is used to make various proteins, and in people with low
to moderate intakes of vitamin B3 (niacin/niacinamide), Tryp
may be used by the liver to make the coenzyme form of B3-NAD-
at the expensive ratio of 60mg Tryp to one mg niacin (8).
In people who are even marginally vitamin B6 deficient, Tryp
may be immediately degraded by the liver into the mildly toxic
metabolites hydroxykynurenine, xanthurenic acid, and hydroxyanthranilic
acid, then excreted in urine (9). Thus, the brain typically
receives less than 1% of ingested Tryp.
Yet even getting its modest share of dietary Tryp is difficult
for the brain, due to the blood-brain barrier (BBB). The BBB
serves as a protection to prevent many toxins, as well as
excesses of nutrients which might temporarily overwhelm and
dysregulate brain function, from entering the brain. 5-HT
itself cannot penetrate the BBB, although Tryp can. Yet the
BBB creates difficulties even for essential nutrients to enter
the brain. Amino acids must be carried through the BBB by
a special transport protein, like passengers on a bus. Unfortunately
for 5-HT using neurons, Tryp must share its "transport
bus" with 5 other amino acids: phenylalanine, tyrosine,
valine, leucine and isoleucine. Tryp is typically outnumbered
about 9:1 in its competition to secure its transport through
the BBB into the brain.
Eating a high protein diet to provide more Tryp only worsens
the problem, by increasing even more the intake of the 5 competing
aminos. Ironically the only dietary strategy which increases
brain Tryp is to eat a high carbohydrate/low protein diet.
When large amounts of carbos are eaten, the body secretes
large amounts of the hormone insulin to lower the ensuing
high blood sugar. Insulin also clears from the blood much
of the 5 aminos that compete with tryp for entry through the
BBB. Insulin has relatively little effect on clearing Tryp
from the blood, however, thus allowing Tryp more space on
the BBB "transport bus," and thus more Tryp reaches
the brain. R. and J. Wurtman reported in 1988 and 1989 that
women suffering from PMS-related depression were found to
spontaneously increase their carbo food and snack intake,
without increasing protein, during their depressive phase,
with a consequent significant decrease in measured depression
ratings, presumably through the insulin-Tryp-5-HT mechanism
(10,11). Unfortunately, insulin also promotes conversion of
the incoming food to stored body fat. Hence the high carbohydrate
diet method of enhancing brain Tryp/5-HT merely trades depression
for obesity and chronic carbo addiction/over consumption.
35 years of research has provided a pair of alternatives to
enhance brain 5-HT levels with consequent lessening of 5-HT
related depression. Many studies have shown both Tryp and
its metabolite, 5-hydroxytryptophan (5-HTP), to be capable
of enhancing brain serotonin and relieving depression when
taken as supplements (12-21).
TRYPTOPHAN SUPPLEMENTS
Taking Tryp as a dietary supplement is the most natural way
to solve the brain's 5-HT production problems. A Tryp supplement,
unlike a high protein diet, will not increase blood levels
of Tryp's 5 amino competitors. Since the normal dietary intake
of tryp is only a gram or so, even a modest amount of supplemental
Tryp (1 to 3 grams) will have a significant effect in boosting
blood and brain Tryp, and hence brain 5-HT levels. Under normal
conditions, the brain enzyme Tryp hydroxylase (TpH) is only
50% saturated (22). TpH is the rate-limiting factor in 5-HT
production, converting Tryp to 5HTP. This means that an increase
in brain Tryp will automatically tend to increase brain 5HTP
production. After TpH converts Tryp to 5HTP, a vitamin B6-dependent
carboxylase enzyme then rapidly converts 5HTP to 5-HT.
However, increased brain production of 5-HT through Tryp supplementation
does not automatically increase 5-HT nerve activity. At low
levels of psychobiologic arousal, there will be adequate serotonin
to support the correlative low 5-HT nerve activity, even when
neuron levels of Tryp and 5-HT are low (22). This more apathetic,
vegetative quiescent variety of depression ("I'm so depressed
I can't even get out of bed") is referred to as the "apathetic-inhibited"
type (22). This form of depression represents more of a deficiency
of activity of the DA/NA "yang" "get-up-and-go",
activating neural circuits, and so Tryp/5-HT may offer little
relief to, or even worsen, this type of depression.
At higher levels of arousal, however, the more rapid turnover
of 5-HT in the synaptic gap will require higher levels of
5-HT production to adequately maintain the greater activity
of 5-HT circuits. Thus Young and Teff suggest that Tryp will
be most effective as an anti-depressant in those suffering
from "anxious-agitated" depression, with its high
state of stress arousal, combined with the depression (22).
Anxious, agitated depression occurs when a person's DA/NA
activating ("yang") neural circuits are functioning
strongly, without the calming, relaxing, mellowing 5-HT circuits
("yin") functioning strongly as a complementary
counterbalance.
The biggest drawback to using Tryp to solve 5-HT deficiency
depression is the activity of the liver Tryp degrading enzyme,
Tryp pyrrolase (TP). TP is known to be activated by two factors
(23). The first is the hormone cortisol. Cortisol, the "state
of siege" stress hormone, is known to be frequently elevated
in the very conditions, such as depression and insomnia, for
which Tryp might be helpful. Taking Gerovital-H3®, low
dose Dilantin, or 7-Keto-DHEA may provide an anti-cortisol
activity to prevent cortisol activation of tryp-destroying
TP.
The other TP-activating factor is- Tryp itself! Tryp is known
to induce and stabilize TP, thus keeping it active in destroying
Tryp as it passes through the liver. Thus Yuweiler and colleagues
point out that successful Tryp antidepressant studies have
generally used low doses (3 grams or less) compared with Tryp
studies having negative results, which have often used high
doses (6-9 grams) (23). The higher doses could ironically
lessen the antidepressant effect of Tryp by hyper activating
liver TP, which would then catabolize incoming Tryp with great
efficiency, canceling out any hoped-for increase in blood/brain
Tryp.
5HTP: TRYPTOPHAN PLUS!
European and Japanese depression research over the past 30
years has focused on 5HTP (Oxitriptan) as a natural solution
to enhance brain 5-HT activity. 5HTP is the intermediate between
Tryp and serotonin. Since the rate-limiting, or problematic,
step in 5-HT production is the conversion of Tryp to 5HTP,
using 5HTP as an antidepressant simply bypasses the production
bottleneck. As Zmilacher and co-authors also note: "L-5-HTP
is not degraded by the tryptophan pyrrolase to kynurenine,
the major pathway for peripheral degradation of L-Tryptophan
(about 98%). Furthermore, L-5-HTP easily crosses the blood-brain
barrier...." (24). Byerley and his co-workers also point
out another key advantage of 5HTP over Tryp: "...administration
of 5-HTP enhances synthesis of serotonin in the brain, but
may also effect noradrenergic [NA] and dopaminergic [DA] neurotransmission.
In laboratory animals as well as human subjects, increased
turnover of dopamine and norepinephrine [NA] occurs after
5-HTP administration." (25)
In a 1984 paper, van Praag also noted the different effects
of tryp and 5HTP on DA/NA neurotransmission. Van Praag found
significant increases in the spinal fluid concentration of
5HIAA, the serotonin-metabolite, after giving both Tryp and
5HTP to different test subjects. Unlike Tryp, which only raised
spinal fluid 5HIAA, 5HTP also raised spinal fluid metabolites
of DA and NA, indicating an activating effect of 5HTP of DA/NA
neurotransmission as well as 5-HT neurotransmission (26).
In a 1983 report, van Praag also demonstrated that among patients
who maintained their antidepressant effect from 5HTP over
the long term, there was evidence from spinal fluid metabolites
of continuing DA/NA activation as well as 5-HT activation.
Among patients whose initial positive response to 5HTP dropped
off after several months, van Praag found a drop in their
initial high levels of DA/NA spinal fluid metabolites as the
5HTP antidepressant effects decreased. When van Praag then
gave these patients supplements of tyrosine, the amino acid
from which DA and NA are made, along with their 5HTP, their
depression once again cleared, while their spinal fluid metabolites
of DA/NA also again increased (27). Van Praag thus demonstrated
that 5HTP is more than just a better Tryp-it is a "Tryp
plus" due to its DA/NA neuroactivation.
In their 1988 review of 5HTP antidepressant studies, Zmilacher
and co-writers report that "Out of the 17 reviewed studies...
60.5% of all the patients (342 out of 565) showed a good or
very good improvement of their depressive state.... A tendency
indicating that L-5-HTP was especially effective in patients
with an anxious agitated depressive syndrome was observed....
An important finding is the very rapid onset of action (within
3-5 days) in patients responding to treatment." (24).
The main drawback to 5HTP use is its gastrointestinal side
effects. "...gastrointestinal symptoms, such as abdominal
cramping, nausea, and diarrhoea, appear to be the most common
adverse effect.... Adverse effects reported infrequently after
oral doses include insomnia, headache and [heart] palpitations."
(25) Zmilacher suggests taking 5HTP with a meal to reduce
GI side effects. Some researchers have suggested that enteric
coated 5HTP, which doesn't dissolve until it reaches the small
intestine, will also reduce GI side effects. (Ed- IAS Oxitriptan
is enteric coated). Some 5HTP researchers give drugs called
"peripheral decarboxylase inhibitors" along with
5HTP, both to reduce GI side effects as well as allegedly
to increase treatment efficacy, yet Zmilacher notes that "A
review of the literature on this subject revealed that L-5-HTP
with a peripheral decarboxylase inhibitor (93 out of 176 patients,
52.9%)." (24) "... psychopathological side effects
[swings from depression to mania or hypomania] have mainly
been reported in patients receiving L-5-HTP in combination
with a peripheral decarboxylase inhibitor." (24)
In 1991 Poeldinger and colleagues reported a landmark double-blind
study that compared 5HTP with the popular SSRI, fluvoxamine
(a Prozac® "cousin"). Not only did 5HTP prove
to be slightly superior to fluvoxamine in antidepressant action,
but 5HTP patients had significantly fewer and less serious
side effects (mostly GI) than patients receiving fluvoxamine
(28). Thus, not only is 5HTP an effective and more natural
alternative to the SSRIs, but it is also less side-effect
prone.
Tryp and 5HTP may be used separately or together to improve
serotonin metabolism. Tryp may best be taken at bedtime, 1-3
grams. 5HTP may be taken with meals, 50-100 mg, once or twice
daily. Initial GI symptoms from 5HTP, if they occur, will
frequently disappear with continued use. If not, then using
only Tryp may still provide adequate 5HT antidepressant effect.
Tryp and 5HTP will potentate the effects of MAOI, TCA and
SSRI drugs, and they may possibly precipitate the "serotonin
syndrome" if combined with these drugs. The fortunately
rare 5-HT syndrome, as reported by H. Sternbach in 1991 (29),
involves extreme hyperactivity of 5-HT neural circuits and
may include confusion, hypomania. agitation, "feeling
drunk," as well as extreme restlessness, muscle twitches,
hyperactive reflexes, intense sweating, shivering, tremor,
diarrhoea, fever and in coordination. Occasionally coma or
death may result. Thus, although Tryp or 5HTP may be useful
to lessen the needed dosage fro those wishing to remain on
standard antidepressant drugs, combining Tryp or 5HTP with
antidepressant drugs, or altering current drug dosages, should
be done ONLY under expert medical supervision to avoid inducing
the serotonin syndrome. Also, one should never suddenly stop
antidepressant drugs and replace them with Tryp or 5HTP. Any
cessation of current antidepressant drug therapy should be
done gradually, and only under expert medical supervision,
to avoid possible depression relapse.
L-DEPRENYL
L-deprenyl (DPR) is a drug developed in the 1960s by Dr. Joseph
Knoll. Research has shown DPR to be a safe and multi-faceted
drug. At doses of 10-15mg/day or less for humans, DPR is a
selective MAO-B inhibitor. MAO-A enzymes break down 5-HT and
NA, while MAO-B enzymes break down DA and phenylethylamine
(PEA). Classic MAOIs, such as phenelzine and tranylcypromine,
inhibit both MAO-A and MAO-B. Classic MAOIs also routinely
suffer from the "cheese effect" - the tendency to
promote serious, even fatal high blood pressure crises from
ingestion of tyramine-rich foods such as aged cheeses and
wines. DPR is remarkably free from the "cheese effect"
even at typically high daily doses of 30-60mg (4,30). DPR
also suppresses the free radical/oxidant stress associated
with increased DA neuron activity, as occurs in Parkinson's
disease (31). DPR protects DA neurons in monkeys from MPTP,
a neurotoxin that has caused rapid-onset Parkinson's disease
in humans who unwittingly consumed it in recreational drugs
(32). DPR has extended the average life span of male rats
beyond the maximum age of death of the species. And DPR has
been successfully used as an antidepressant.
In 1980 Mendelwicz and Youdin reported results from a double-blind
study comparing placebo, 300mg 5HTP, and 5HTP plus DPR. The
18 patients receiving DPR plus 5HTP experienced depression
relief significantly greater than those receiving placebo
or 5HTP alone (34).
Quitkin and co-workers found DPR to be superior to placebo
in a 6 week trial with 17 atypical depressive patients, and
relatively free of side effects. 9/10 positive DPR responders
required a 30mg/day DPR dosage. At doses above 20mg, DPR is
no longer a selective MAO-B inhibitor, but also begins to
suppress MAO-A activity as well, as do standard MAOIs. 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 MAOIs tolerated
a six-week regimen of L-deprenyl quite well." (4)
J. Mann and colleagues reported positive antidepressant effect
with DPR in a 44-patient double blind study in 1989. "...after
six weeks and at higher doses (averaging about 30mg/d fro
the second three weeks), [DPR] 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 occurrence of
side effects with [DPR] was no greater than with placebo....
[DPR] 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 DPR at 60mg/day dosage, T. Sunderland and co-workers
reported in 1994 that "Selegiline [DPR] 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 DPR 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, that
used very modest DPR doses of 5-10mg/day. At this low dose,
DPR 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 - 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 (10mg) 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 DA/NA over-activation uncompensated
for by counterbalancing serotonin activation - Tryp would
have been appropriate to complement the DPR/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 DPR/day, 100 mg vitamin B6/day, and 1 gram phenylalamine
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 phenylalamine 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 DPR/phenylalamine
treatment to enhancement of phenylethylamine (PEA) metabolism.
PEA and DA are the main substrates for MÅO-B, which
DPR inhibits. PEA is formed from phenylamine with the help
of a B6-activated enzyme. PEA is a trace amine that may potentate
neuronal firing rates of NA/DA neurons, especially when they're
underactive (37). Sabelli has shown that depressives have
significantly lower blood and urine levels of PAA (the chief
PEA breakdown 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, phenylalamine can also
be converted into the two "yang" neurotransmitters,
NA and DA (39). Thus, a low dose DPR (5-10 mg), moderate dose
l-phenylalamine (250 - 500 mg once or twice daily) and 50
-100 mg dose of vitamin B6 regimen may serve to enhance mood,
drive, and energy in the "apathetic-inhibited" type
of depression, while Tryp 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 from 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 "lynch-pin"
of oxidative energy metabolism (40).
NADH is also the indirect activator of tyrosine hydroxylase
(TH), the rate-limiting enzyme in the formation of DA and
NA. TH converts the amino acid tyrosine into L-dopa. It can
also convert phenylalamine into tyrosine. DA neurons convert
L-dopa into DA, while NA neurons convert L-dopa first to DA,
then into NA.
The coenzyme that activates TH 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 TH an dDA/NA
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,
tyrosinehydroxylase 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
DA/NA production, 5-10 mg NADH, taken once or twice daily
on an empty stomach, may serve as a useful complement to the
DPR/phenylalanine program or may be simply used as a single
therapy.
GEROVITAL: GH3
Gerovital-H3® (GH3) (specially stabilized procaine) was
developed in the 1940s by Ana Aslan 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 iproniazid and phenelzine, are strong,
irreversible, non-competitive 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 hydrolysed 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 DA, NA, and 5 HT 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 TCA 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 hypercorisolism
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 Tryp pyrrolase, the Tryp-destroying
enzyme, GH3's ability to reduce cortisol may also provide
antidepressant effect through enhancing brain Tryp, and hence,
brain 5-HT 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-adenosylmethionine (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 phosphatidye choline
(55). SAMe has been shown to significantly increase cerebrospinal
fluid levels of HVA and 5HIAA, the chief metabolites of DA
and 5-HT. SAMe has been shown in antidepressant studies to
possess mood-elevating and behaviorally arousing effects due
to the SAMe-increased DA and 5-HT activity, and due to a selective
excitatory action on cortical neurons in the brain (48).
In 1994 G.M. Bressa reported a meta-analysis of 31 prior studies
of SAMe's antidepressant effects. "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 GI effects seem
to be mediated through the brain - they are not the result
of direct GI tract irritation. SAMe actually inhibits and
protects against GI lining damage and irritation. The other
occasionally reported side effect of SAMe is mania or hypomania
- i.e. excessive mood elevation and over stimulation. This
side effect is reported far more rarely than the GI 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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