Food And Nutrients In Disease Management

By Author: Marty Hinz
Total Articles: 13
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I. INTRODUCTION

Since amino acids obtained from dietary sources are the precursors of mood-regulating neurotransmitters such as serotonin and dopamine, amino acids are considered to hold potential in treating
depression. Neurotransmitter precursors are the subject of ongoing research.So why is this topic relevant to primary care medicine? Patients have taken matters into their own
hands. Patients are self-treating their depression with amino acid supplements and appear to be motivated by a perceived benefi t in their mood and overall health. The amino acid precursors tryptophan,
tyrosine, 5-hydroxytryptophan, and L-dopa are readily available as supplements at doses that exceed feasible dietary intake. Amino acids supplements have less potential for harm and larger therapeutic
effect when their use is physician-guided.This chapter presents the bundle damage theory of depression to probe the biologic basis of amino acid therapy. It offers primary care physicians a treatment protocol that implements laboratory testing to
guide dosing; explains the potential side effects and how these ...
... can be minimized; offers quality regulation in product selection; and presents a protocol for simultaneous use of medication and nutrients in
the treatment of clinical depression.

II. EPIDEMIOLOGY
Depression is a global problem. The World Health Organization notes:32 Nearly 5-10% of persons in a community at a given time are in need of help for depression. As much
as 8-20% of persons carry the risk of developing depression during their lifetime. The average age of the onset for major depression is between 20 and 40 years. Women have higher rates of depression than
men. Race or ethnicity does not infl uence the prevalence of depression. World wide depression is the fourth leading cause of disease burden, accounting for 4.4% of total Disability-Adjusted Life-Years
(DALYs) in the year 2000. It causes the largest amount of non-fatal burden. Disability from depression world wide is increasing. In 1990, the total years lived with disability (YLD) was 10.7%. By 2000, the
YLD had increased to 12.1% worldwide.33 Mental health conditions have a tendency to move upwards in ranking, while ranked as the fourth leading cause of disease burden in 2000, it is expected that
depression will move to second place by 2020, second only to heart disease.34 Population surveys suggest that while the incidence of depression is higher in the developed
countries of North America and Europe than in other regions, it is nonetheless a common condition throughout the world.38 The rate difference is often attributed to underdiagnosis, but newer data
suggest that the Western diet, stressful lifestyle, and higher toxicant exposures contribute to the prevailing high rates in Westernized countries.32
The monoamine theory fails to explain why the incidences of depression are increasing on a worldwide basis and is more prevalent in developed countries

III. PATHOPHYSIOLOGY

The monoamine theory
The monoamine theory of depression has long been the major framework against which the treatment of depression has been examined and developed due to the fact that the theory attempts to
provide a pathophysiologic explanation for depression and the actions of antidepressants. The central premise of the monoamine theory states that it may be possible to restore normal function in
depressed patients by targeting the catecholamine and/or serotonin systems with antidepressants.This theory is based on evidence that depression symptoms can be improved by administering
compounds that are capable of increasing monoamine concentrations in the nerve synapses. Early research focused on defi cits in the catecholamine system with specifi c emphasis on noradrenalin
as a potential cause for depression. With further research, the theory was expanded to include the serotonin system as a cause for depression. This research has led to the use of drugs for treatment of
depression that affect changes in monoamine uptake and enzymatic metabolism.1 While many of the depression treatments based on the monoamine theory appear to be initially
useful, many of them lack the short-term and long-term effi cacy needed for relief of symptoms in most patients. In several studies of reuptake inhibitors administered, only 8% to 13% of subjects
obtained relief of symptoms greater than placebo. Remission rates for escitalopram compared to placebo in adults was studied (48.7% vs. 37.6%, P = 0.003). Here, 11.1% of subjects obtained relief
greater than placebo.35 Remission rates for citalopram versus placebo in another study were studied (52.8% vs. 43.5%, P = 0.003). Here, 9.4% of patients obtained relief greater than placebo.35
Venlafaxine-XR was similar to escitralopram and citalopram (P = 0.03).35 Treatment of the elderly in the primary care setting under the monoamine theory reveals no relief
of symptoms versus placebo. In the elderly (79.6 years, SD = 4.4, N = 174), it was concluded that citalopram, was not more effective than placebo for the treatment of depression.27 In treatment of
depression in patients over 60 years of age with a mean age of 68 years, Escitalopram treatment was not signifi cantly different from placebo treatment (N = 264).29
Depression treatment of children and adolescents ages 7 to 17 (N = 174) with citalopram, under a double-blind 20 mg/day, 40 mg/day option, found 24% of patients treated with placebo showed
improvement versus 36% of patients taking citalopram.28 Other studies of other reuptake inhibitors revealed similar results.50-55 Reuptake inhibitors are effective in treating other disorders than those for which they were initially
developed, such as obesity, panic disorder, anxiety, migraine headaches, ADHD/ADD, premenstrual syndrome, dementia, fi bromyalgia, psychotic illness, insomnia, obsessive-compulsive
disorder, and bulimia/anorexia; yet not all drugs that increase serotonin or catecholamine transmission are effective when treating depression.1
Treatment with reuptake inhibitors is based on the monoamine theory, which does not explain why most subjects studied achieve results no better than placebo and why treatment is much less
effi cacious in the elderly. Neither does it explain the effi cacy of treating other conditions. In sum,the mechanism and corresponding medication for the treatment of depression suggest there may be
more to the underlying pathophysiology.

Parkinsonism Model
Insights into the pathophysiology of depression can be gained from understanding another monoamine neurotransmitter disease, Parkinson's disease. Parkinsonism is caused by damage to the
dopamine postsynaptic neurons of the substantia nigra at levels that result in clinical compromise of fi ne motor movement.Parkinson's disease has a study model of neurotoxin damage.49 A great deal of understanding about
Parkinson's disease has resulted from research and case studies involving the neurotoxin MPTP (1-methyl4-phenyl 1,2,3,6-tetrahydropyridine). In 1982, the fi rst writings on MPTP appeared in the medical literature after several heroin addicts administered synthetic heroin (MPPP) that contained the byproduct
of synthesis, MPTP.9 Since that time, the MPTP mechanism of action has become the prototype in the study of Parkinson's disease. At present, most medical school students study the ability of MPTP to
quickly induce advanced Parkinson's symptoms in patients without prior history of the disease.MPTP is a free radical neurotoxin, which interferes with mitochondrial metabolism and leads
to cell death (apoptosis). It freely crosses the blood-brain barrier and has an affi nity for the postsynaptic dopamine neurons of the substantia nigra, which it destroys. MPTP is chemically similar
to MPPP (synthetic heroin) and may be produced as a byproduct during the illegal manufacturing of MPPP and other narcotics.9 The MPTP model of Parkinson's disease has taught us a lot about
the dopamine neurons of the substantia nigra. The main point is that if enough dopamine neurons are damaged, the fl ow of electrical impulses is compromised and Parkinson's symptoms will occur.
The way to compensate for neurotoxin-induced damage is to increase neurotransmitter levels higher than is normally found in the system.9 Consistent with the fi ndings of the MPTP model, the pharmacologic treatment is dopamine
agonists, which raise the existing levels of this neurotransmitter above population norms in order to boost damaged neurons. Dopamine agonists, such as bromocriptine, pergolide, ropinirole, pramipexole,
and cabergoline can be used as a monotherapy or in combination with L-dopa. L-dopa crosses the blood-brain barrier and is freely synthesized into dopamine without biochemical regulation.3
The elevation of dopamine in the central nervous system stimulates the remaining viable dopamine neurons of the substantia nigra by increasing the electrical fl ow, which results in restoration of the
regulator function of the dopamine bundles and improvement of disease symptoms.7 The shortcoming is tachyphylaxis, where the dopamine agonist and/or L-dopa become ineffective.
With Parkinson's patients, establishing dopamine levels in the reference range reported by the laboratory does not provide relief of symptoms. For example, the reference range of urinary dopamine
reported by the laboratory is 40 to 390 micrograms of dopamine per gram of creatinine (the neurotransmitter-creatinine ratio compensates for dilution of the urine). In our years of research,
we have not observed a patient with Parkinson's who was able to achieve relief of symptoms with dopamine levels in this range. For treatment of patients with Parkinson's, the therapeutic range of
urinary dopamine is 6000 to 8000 micrograms of dopamine per gram of creatinine. Dopamine levels of this magnitude can be achieved by administration of the amino acid precursor, L-dopa.
Amino acid supplementation can reduce the tachyphylaxis generally associated with pharmacologic interventions. Once the synaptic levels of dopamine are high enough and the fl ow of electricity is
once again adequate to regulate fi ne motor control, clinical resolution of the Parkinsonian tremor and other symptoms are seen.40 As with Parkinsonism, the damage to other neuron bundles of the serotonin/catecholamine pathways
as seen in depression can be dealt with effectively by increasing the neurotransmitter levels higher than is normally found in the system. This has led our group to propose the Bundle Damage
Theory of Depression.

The bundle damage theory
The bundle damage theory states:Neurotransmitter dysfunction disease symptoms, such as symptoms of depression, develop when the electrical fl ow through the neuron bundles that regulate function is compromised by damage to the
individual neurons or the neuron components composing the neuron bundle which conducts electricity to regulate or control function. In order to optimally restore neuron bundle regulatory function, synaptic
neurotransmitter levels of the remaining viable neurons must be increased to levels higher than is normally found in the system, which restores adequate electrical outfl ow resulting in relief of symptoms
and optimal regulatory function.
Bundles of neurons convey electricity that regulates and/or controls numerous functions in the body. If enough of the individual neurons of a bundle become damaged the fl ow of electricity through the bundle is diminished, leading to the function being controlled and/or regulated not controlling
properly, causing symptoms of disease to develop. Technically synaptic neurotransmitter levels prior to treatment in patients with disease due to neuron bundle damage are in the normal range for the
population.The bundle damage theory and the monoamine theory are not mutually exclusive of each other.Instead these two theories can be viewed a complementary in that they address different mechanisms
of action leading to neurotransmitter dysfunction and compromised electrical fl ow out of the postsynaptic neuron. The monoamine theory addresses low levels of neurotransmitters in the
synapse as the etiology of impedance of electrical fl ow needed to regulate function and keep disease symptoms under control. The bundle damage theory addresses damage to the primarily
postsynaptic neuron structures that impede the fl ow of electricity needed to regulate function and keep disease symptoms under control. With the monoamine theory and the bundle damage
theory the fl ow of electrical energy needed to regulate function is not adequate. Differentiation of the two theories lies in the etiology of the dysfunction. Under monoamine theory returning
neurotransmitter levels to normal will relieve disease symptoms. Under the bundle damage theory synaptic neurotransmitter levels need to be established that are higher than the reference range of
the population.It is the mechanical damage to the postsynaptic neurons as suggested by the bundle damage theory and not the synaptic neurotransmitter levels that is the primary cause of monoamine disease.
This subset is composed of about 88% of adult patients and 100% of the elderly patients with depressive symptoms—the nonresponders from the depression studies above.
Neurons are intended to function for life. Loss of a neuron to apoptosis is permanent, although in limited areas of the brain neurons may regenerate to replace the neurons that have undergone
apoptosis.58 As neurons go into apoptosis in the postsynaptic neuron and become completely nonfunctional they tend to go through an agonizing death where the electrical brilliance with which
they function slowly fades until the electrical fl ow through the neuron regulating function decreases and stops over time.The only way to increase neurotransmitter levels in the central nervous system is to administer
amino acid precursors that cross the blood-brain barrier and are then synthesized into neurotransmitters.Increasing neurotransmitter levels in the synapse is analogous to increasing the voltage in
an electrical wire, whereby turning up the voltage you get more electricity out of the other end of the wire. Turning up the voltage increases the electrical potential (pressure) of the electrons entering a
partially damaged wiring connection, leading to more electrons (electricity) fl owing out of the other end. In the case of neurotransmitter disease where the neurons of the neuron bundles are damaged
to the point that the electricity fl owing out of the neuron bundles is diminished disease develops.Increasing neurotransmitter levels will effectively increase voltage in the remaining viable neurons
in the bundle, causing electrical fl ow out of the damaged neuron bundles to increase to the point that normal regulation and/or control is once again observed. In this state, from a clinical standpoint, the
symptoms of disease are under control.

Etiology of Bundle Damage

Bundles of monoamine neurons can be impaired from neurotoxin exposures, trauma, or biologicalinsult.56 Neurotoxin exposures are poorly defi ned and ongoing exposures are in contrast to
the MPTP study model of Parkinsonism. The most comprehensive listing located reveals 1179 known neurotoxins.39 Susceptibility of individuals based on genetic predisposition, environmental
infl uences, synergy between chemicals or other predisposing factors suggest that some individuals may experience neurotoxicity from many unlisted substances and at lower than threshold doses
of known neurotoxins, and so was not considered. Under the bundle damage theory it is assumed that neurotoxins are the leading cause of monoamine bundle damage leading to the following
speculation: Depression The bundle damage's theory of repeated insult during a lifetime can explain the lack of effi cacy seen in the treatment of elderly with reuptake inhibitors who presumably have greater cumulative lifetime
effects from neurotoxins and other events that cause neuron damage. In the end these patients need to have neurotransmitter levels established that are much higher than can be achieved with reuptake
inhibitors alone.With repeated insult more damage occurs, which is cumulative. When the damage is at the point where the neurotransmitter levels needed to control disease symptoms cannot be achieved with the
use of reuptake inhibitors alone, from a clinical standpoint it appears that the drug is not working.This may explain why about 90% of adults treated with reuptake inhibitors achieve results no better
than placebo.The bundle damage theory may also explain why developed countries have a higher rate of depression as the population is exposed at a higher rate to neurotoxins.
Since insult exposure may be ongoing in patients with depression, optimizing nutritional status is important. Improving neuronal ability to minimize and recover from toxic insult form the basis
of the antioxidant nutrients Dr. David Perlmutter explains in Chapter 28, Parkinson's Disease, and the membrane-stabilizing nutrients Dr. Patricia Kane explains in Chapter 24, Seizures.

IV. PHARMACOLOGY

AMINO ACIDS
Treatment of depression, as well as any other monoamine neurotransmitter diseases, is not possible through the direct administration of monoamine neurotransmitters. This is due to the fact that monoamine
neurotransmitters do not cross the blood-brain barrier, as depicted in Figure 29.1.2,3,4,5 The only way to increase the levels of central nervous system monoamine neurotransmitter molecules is
to provide amino acid precursors, which cross the blood-brain barrier and are synthesized into their respective neurotransmitters by presynaptic neurons.

REUPTAKE INHIBITOR DEPLETION OF MONOAMINE

The National Institute of Drug Abuse presents a detailed discussion on its website on how reuptake inhibitors deplete neurotransmitters.22 Medicines used to treat depression are not the only drugs
that block reuptake; cocaine and amphetamines block reuptake as well.22 Reuptake inhibitors block
CONCLUSIONS

The bundle damage theory creates a framework by which to offer patients new treatments for clinical depression. The theory underscores the importance of minimizing toxic exposures, through
avoidance where possible, through diminished uptake, and through adequate nutrients. Similarly patients who have inadequate substrate for neurotransmitter synthesis may need cofactors, nutrients
involved in sulfur pathways, and amino acid precursors. Patients may also receive benefi t from amino acid precursors beyond what can be obtained from diet alone.
There are three primary considerations in the use of amino acids for treating depression.First, proper levels of amino acids should be administered with the drugs to prevent depletion of
neurotransmitters. Second, proper use of amino acids will keep the drug functioning properly, avoiding tachyphylaxis. Third, the use of amino acids may cause a drug side effect to become
active. In summary, amino acids hold more therapeutic potential and less potential for harm when
administration is physician-guided.