Food and Nutrients in Disease Management
<b>I. INTRODUCTION</b>
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.
<b>II. EPIDEMIOLOGY</b>
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
<b>III. PATHOPHYSIOLOGY</b>
<b>The monoamine theory</b>
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.
<b>Parkinsonism Model</b>
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