Updated: 06/30/2006 - LEF/Life Extension Foundation
Depression is considered the most common cause of disability in the
United States (Norman TR 2006). According to the National Institutes of
Health, clinical depression will affect up to 25 percent of women in
their lifetimes and up to 12 percent of men. People with depression
suffer in many areas of their lives, including sleep, eating,
relationships, school, work, and self-image.
Depression is more than the normal feelings of sadness that people
experience from time to time. It is a clearly defined disorder that
affects both mind and body. People suffering from clinical depression
cannot just will their blues away, and in most cases the depression
will not subside without active intervention. Unfortunately, however,
many people do not seek professional treatment for their depression, so
the disorder is likely to be underdiagnosed. Among those who do seek
professional help, many people do not find relief for their condition
among conventional therapies.
Treatment for depression is usually multifaceted, and there is no
doubt that nutrition plays an important role. Research has shown that
the body chemistry of depressed people is altered in various ways and
that deficiencies in neurotransmitters, hormonal imbalances, and other
nutritional deficits can contribute to clinical depression. Also, many
people with depression do not eat enough, overeat, or eat nonnutritious
foods. New research has also connected depression to inflammation and
oxidative stress, which are both appropriately managed with nutritional
supplements.
Finally, the role of hormones in depression is underappreciated in
the medical community. Many people who suffer from depression that
cannot be treated effectively with conventional antidepressants may
actually be suffering from hormonal imbalances that are causing their
disease. Unfortunately, few physicians routinely test their depressed
patients for hormonal imbalances.
Ultimately, the treatment of depression usually touches on many
facets of a person’s life. Exercise is important, and treatments such
as massage and acupuncture have a long history of effectiveness when
used as part of a treatment program. Counseling and psychiatric therapy
can also help people deal with the feelings of anxiety and hopelessness
that accompany depression.
The good news is that depression can be treated successfully. Many
people who seek treatment for their depression realize they may have
been suffering its symptoms for a long time and respond favorably to
treatment.
Diagnosing Depression
In recent years, researchers have identified various kinds of
depression, including major depressive disorder, dysthymic disorder,
bipolar disorder, seasonal affective disorder, postpartum depression,
and premenstrual dysphoric disorder (PMDD). For more information on
seasonal affective disorder and PMDD, please see the chapters in this
book pertaining to those topics. This chapter will focus on major
depressive disorder, and the term depression will be used to refer to
major depressive disorder.
Major depressive disorder is sometimes called major depression,
clinical depression, or unipolar depression. Unipolar depression is so
named because the disorder is characterized only by depression, as
opposed to bipolar disorder, which is characterized by both depression
and episodes of mania. People with major depressive disorder may have
recurrent episodes of depression, and there is evidence that many
people experience their first episodes of depression at a young age
(Kessler RC et al 1998; Larsson B et al 1998). Episodes of depression
may be separated by years or months and may become more common as a
person ages. After an episode is over, most people will recover
completely. People who recover only partially are more likely to
experience another episode. Among adolescents, clinical depression is
associated with substance abuse and suicide (Kessler RC et al 1998),
and even among adults, as many as 15 percent of people diagnosed with
depression die by suicide. Clinical depression is also associated with
vascular and cerebrovascular disease (Thomas AJ et al 2003, 2004;
Tiemeier H 2003).
Guidelines for the diagnosis of depression can be found in the
fourth edition of the American Psychiatric Association’s Diagnostic and
Statistical Manual of Mental Disorders. To be diagnosed with clinical
depression, the patient must experience at least five of the nine
symptoms below for two weeks or more, most of the time, almost every
day. The symptoms must include either a depressed mood or loss of
interest.
- Depressed mood
- Reduced level of interest or pleasure in activities
- A considerable loss or gain of weight or appetite
- Insomnia or excessive sleeping
- Behavior that is agitated or slowed down
- Fatigue or diminished energy
- Thoughts of worthlessness or guilt
- Reduced ability to think or concentrate
- Frequent thoughts of suicide or death, or suicide attempts
In addition, the following conditions must be present:
- The symptoms are not part of a mixed episode of psychiatric disorders.
- The symptoms are a cause of distress at home, work, school, or other social settings.
- The symptoms are not caused by a substance, including alcohol or illicit drugs.
- The symptoms are not caused by normal bereavement, they continue
for more than two months, or they cause difficulty in functioning.
The causes of clinical depression are not fully known. It is likely
that several factors, including a genetic predisposition and hormone
imbalances, work together in any particular individual to bring on a
depressive episode. One of the leading factors associated with
depression is reduced levels of norepinephrine, serotonin, and dopamine
(the so-called amine theory) (Hou C et al 2006; Prange AJ et al 1974).
There is also evidence that the structure of the brain itself may be
altered in depression, especially the hippocampus (Campbell S et al
2004), although few studies have been conducted on effective treatment
for these changes. Other factors that may contribute to depression
include oxidative stress, which can cause cell membrane and DNA
destruction in the brain (Khanzode SD et al 2003), inflammation
(Elenkov IJ et al 2005), and hyperactivity of the
hypothalamic-pituitary-adrenal (HPA) axis (Antonijevic IA 2006).
The Problem with Conventional Treatment of Depression
Conventional medicine’s track record in treating depression has
improved in recent decades, but many patients are still unable to find
relief from their condition with conventional antidepressants, or they
face the prospect of unpleasant and even dangerous side effects from
their therapy. In 2004, for example, a federal advisory panel announced
its safety recommendations for the newest and most common class of
antidepressants, selective serotonin reuptake inhibitors (SSRIs).
The panel found that SSRIs not only increase the risk of suicide for
some younger patients but are often ineffective. The panel urged the
Food and Drug Administration (FDA) to impose its strongest
caution—known as a black box warning—regarding the use of this class of
antidepressants in children and adolescents (Food and Drug
Administration 2004). In October 2004, the FDA adopted the
recommendation and mandated warnings for all SSRI drugs.
The panel’s investigation came on the heels of several highly
publicized incidents in which children and adolescents on the drugs
committed suicide, and it highlighted the downside of antidepressant
drugs. Although only Prozac® is approved by the FDA for the treatment
of depression in children and adolescents, they are often given
prescriptions for other medications, such as Zoloft®, Paxil®, and
Celexa®. All of these drugs belong to the SSRI class of antidepressants
and are believed to work similarly.
The debate in the United States was prompted in 2005, when British
officials banned all SSRIs except Prozac® for use in children. Despite
that action, most experts agree it is unlikely that Prozac® is
inherently safer than other SSRIs for use in children and adolescents.
Although the various SSRIs differ chemically, their mechanism of action
in the body is essentially the same. All inhibit activity at structures
known as uptake pumps, located on nerve endings. Most affect the
reuptake of serotonin from the synapses, or spaces, between nerve
endings. Some affect another messenger chemical, norepinephrine, in a
similar manner. These drugs are known as serotonin norepinephrine
reuptake inhibitors.
Serotonin and norepinephrine are neurotransmitters that regulate
mood, sleep, appetite, and emotion and are involved in a variety of
physiological and behavioral functions. If the immediate reuptake of
serotonin (or norepinephrine) is prevented, more of these precious
brain chemicals remain available to do their intended work (Vaswani M
et al 2003; Bourin M et al 2002).
Antidepressant Therapy’s High Cost
Unfortunately, even in adults, the depression relief afforded by
SSRIs often comes at a steep price, and not just in monetary terms,
though most SSRIs are far from inexpensive. The list of potential side
effects includes headache, nausea, diarrhea, anxiety, sleep
disturbances, weight gain, fatigue, and most common of all, sexual
dysfunction (Degner D et al 2004; Wilson K et al 2004; Gregorian RS et
al 2002). The latter strikes up to 60 percent of patients taking SSRIs
and usually manifests as loss of libido, insufficient lubrication or
arousal, or an inability to achieve orgasm (Clayton AH et al 2002;
Gregorian RS et al 2002). Among men who experience sexual side effects,
erectile dysfunction occurs in up to 90 percent of cases (Rosen RC et
al 2003). Understandably, many patients find this side effect
particularly distressing.
Drug interactions with antidepressants are also a concern. Alcohol,
the most common drug of all, may be especially risky. It causes
potentially perilous sedation when mixed with antidepressants. Because
of these side effects, many patients discontinue their medication and
risk sinking back into depression. Not all patients respond to SSRIs,
even when they follow the dosage recommendations of the prescribing
physician. Treatment failures range from 40 to 60 percent, and relapse
rates are similarly discouraging. According to a recent report from
Duke University Medical Center, an analysis of more than a decade of
research on the subject shows that recurrence and relapse rates for
drug-treated depression range as high as 80 percent (Masand PS 2003).
The same report noted that up to 44 percent of patients starting drug
therapy discontinue the drug within three months. Many patients (28
percent) discontinue drug therapy due to intolerable side effects,
often within the first month, before the drug takes effect (Masand PS
2003).
Although they are not perfect, SSRIs are a vast improvement over
previously available drugs and therapies for depression. In the first
half of the 20th century, physicians could offer little more than talk
therapy or electroconvulsive therapy (ECT) as treatment for their
patients with major depression. Although the former was often
ineffectual, the latter works very well. However, ECT is time
consuming, requires multiple treatments, and often produces some memory
loss, as the brain is literally zapped with electrical current.
Understandably, a certain amount of stigma is associated with the use
of ECT. According to a survey of thousands of Consumer Reports
subscribers who had recently undergone treatment for depression, talk
therapy, while often useful, may require at least 13 sessions to
achieve relief comparable to that available through drug therapy (Drugs
vs. Talk Therapy 2004).
Thus, when the first true antidepressant drug, a monoamine oxidase
inhibitor, was introduced in the 1950s, doctors hailed the dawn of a
hopeful new era in the treatment of depression. However, monoamine
oxidase inhibitors are particularly risky drugs; their side effects are
numerous and often severe, and drug interactions are potentially fatal.
The advent of tricyclic antidepressants in the 1960s marked a further
advance in treatment. But even tricyclics, such as imipramine and
amitriptyline, come with unpleasant side effects. Dosages must be
carefully monitored because therapeutic ranges are narrow and overdoses
are potentially fatal. Side effects tend to manifest quickly, but onset
of action can take so long (from four to six weeks) that many patients
discontinue the drug long before experiencing mood elevation (Masand PS
2003; Nemeroff CB 2003).
Balancing Hormones
A survey of the scientific literature suggests that one reason
antidepressants have such a high failure rate is that the role hormones
play in the disease is underappreciated. In fact, hormones are
well-known regulators of mood, and many, such as dehydroepiandrosterone
(DHEA), are present in large quantities in the brain. For example,
estrogen, alone or in combination with antidepressant drugs, has been
shown to improve mood, whereas progesterone affects mood and memory
adversely (Birzniece V et al 2006). Among men, declining hormone levels
caused by aging are associated with depressed mood (Amore M 2005).
These findings are important because they offer an alternative
avenue of therapy for people who may not receive adequate relief from
conventional medicines. Both men and women are affected by declining
hormone levels as they age (menopause in women and andropause in men).
Hormone replacement therapy seeks to reestablish the hormone levels of
a healthy young adult. It is important to understand that no single
hormone exists in a vacuum. The major sex hormones are all synthesized
from cholesterol, and they exist in a cascade in which a change in one
hormone affects levels of other hormones. Thus, if you and your
physician are considering hormone replacement therapy, it is important
to test for all the hormones, including pregnenolone, DHEA, estrogen,
progesterone, and testosterone, and design a comprehensive program of
bioidentical hormone replacement.
DHEA. DHEA is an important steroid hormone whose
levels decrease with age. People with depression have low levels of
DHEA, and DHEA has been shown to modulate serotonin levels in the
brains of laboratory rats (Karishma KK et al 2002; Abadie JM et al
1993). A number of studies have examined the role of DHEA in
depression, with very encouraging results. In one study, patients with
HIV/AIDS and depression benefited significantly from DHEA therapy
(Rabkin JG et al 2006). In a randomized, placebo-controlled,
double-blind study that lasted for six years, researchers tested 90 mg
DHEA daily for 3 weeks and 450 mg/d for 3 weeks as a monotherapy for
both mild and severe depression. They found that DHEA therapy resulted
in a significant improvement in symptoms, compared with placebo
(Schmidt PJ et al 2005).
Testosterone. Studies indicate that levels of
testosterone are reduced in some depressed men (Barrett-Connor E et al
1999; Schweiger U et al 1999). A clinical trial using transdermal
testosterone gel showed that patients treated with testosterone
experienced significant improvements in depressive symptoms (Pope HG Jr
et al 2003).
Estrogen. Estrogen is also linked to depression. It
is of particular importance in perimenopausal or postmenopausal women
(Grigoriadis S et al 2002). Women using estrogen replacement therapy to
alleviate menopause symptoms appear to experience reduced depression
(Miller KJ et al 2002). In some older women being treated for
depression, estrogen replacement therapy may actually improve the
effects of conventional antidepressants (Schneider LS et al 2001).
Estrogen is thought to produce its antidepressant effects by
regulating serotonin in the central nervous system (Joffe H et al 1998;
Rubinow DR et al 1998). Estrogen is also thought to reduce monoamine
oxidase activity, increasing levels of neurotransmitters. Animal
studies show that removing estrogen eliminates downregulation of
serotonin receptors produced by antidepressants, an effect that is
reversed with reintroduction of estrogen. This suggests that estrogen
affects antidepressant activity and modulates serotonergic transmission
within the central nervous system (Bethea CL et al 1998; Kendall DA et
al 1982).
Homocysteine and Depression
Many nutrients and supplements can influence the body’s management
of vital neurotransmitters. Much like the prescription drugs used to
treat depression, these natural therapies act by increasing production
of neurotransmitters or reducing their rates of degradation. Unlike
prescription drugs, however, natural therapies can also minimize the
effects of oxidative stress and inflammation that contribute to
depression.
One intriguing target for therapy is homocysteine, which is an
intermediary amino acid that has been associated with various disease
states. Studies have shown that elevated homocysteine is also
associated with depressive disorders and anger attacks caused by
depression (Chen CS et al 2005).
Homocysteine levels can be lowered by the following nutrients, some
of which (especially S-adenosyl-L-methionine, or SAMe) have been found
to improve depression independently.
Folic acid. Clinical trials have demonstrated that
folic acid relieves depression on its own and enhances the
antidepressant effect of conventional antidepressants. In one study,
patients given 500 mcg folic acid daily in conjunction with fluoxetine
experienced a significant improvement in depressive symptoms compared
with patients receiving the antidepressant alone, and women benefited
particularly (Coppen A et al 2000). Because relapse is associated with
low serum folate, it is important to maintain folate supplementation
for a year following a depressive episode (Morris MS et al 2003).
Vitamin B12 (cobalamin). Deficiency in vitamin B12
has been cited as a risk factor for developing depression (Gottfries CG
2001) and is associated with increased homocysteine (Parnetti L et al
1997; Stabler SP et al 1990). People with high vitamin B12 levels have
better treatment outcomes for major depression (Hintikka J et al 2003).
Vitamin B12 supplementation is important for depressed individuals,
particularly older patients, in whom low vitamin B12 levels are common
(Lindeman RD et al 2000; Penninx BW et al 2000).
Vitamin B6 (pyridoxine). In 2005, a team of
researchers from Yale University examined all the published studies on
vitamin B6 and depression. Although the researchers did not find
evidence of benefits from vitamin B6 treatment in the results of all
the studies, they did find that premenopausal women suffering from
depression benefited from vitamin B6 (Williams AL et al 2005).
Trimethylglycine and zinc. Trimethylglycine (TMG)
operates along a different pathway from that of the B vitamins. In
fact, some individuals who have a severely elevated homocysteine level
respond only to TMG because its activity is limited to the liver and
kidneys. To decrease a severely elevated homocysteine level, repeated
high doses of TMG must be taken throughout the day. One small study
found that TMG supplementation taken concurrently with vitamin B6 and
folic acid significantly reduced homocysteine (Dudman NP et al 1996).
Zinc acts in concert with vitamin B6 to promote remethylation of
homocysteine to methionine. Zinc is also needed for the conversion of
homocysteine to cysteine and glutathione.
SAMe. SAMe is derived directly from methionine. Its
job is to provide methyl groups for reactions throughout the body,
including the methylation of nucleic acids (RNA and DNA), proteins, and
structures throughout the brain. SAMe is the precursor to such
nutrients as creatine, glutathione, taurine, L-carnitine, and melatonin
and can be found in almost every tissue in the body. Clinical trials
comparing both oral and intramuscular forms of SAMe to tricyclic
antidepressants show SAMe to be as effective as tricyclic
antidepressants in reducing depressive symptoms (Mischoulon D et al
2002; Pancheri P et al 2002). SAMe is associated with fewer adverse
events (Pancheri P et al 2002) and is better tolerated than
conventional antidepressants (Delle CR et al 2002). Studies show a
significant correlation between plasma levels of SAMe and improvement
of depressive symptoms (Bell KM et al 1994). Some researchers propose
that SAMe produces its antidepressant effects faster than conventional
antidepressants and may potentiate the effects of tricyclic
antidepressants (Mischoulon D et al 2002). It has been studied in the
treatment of depression, schizophrenia, demyelination diseases, liver
disease, dementia, arthritis, and other conditions. It is also
necessary for normal circadian rhythms. High doses of SAMe, 1600 mg
daily, increased phosphocreatine levels in the human brain (Silveri MM
et al 2003), indicating that SAMe is important in forming creatine.
Although SAMe is part of the methionine cycle, taking supplemental SAMe
does not increase the production of homocysteine. It does, however,
encourage the conversion of homocysteine to cysteine and glutathione
(Devlin TM 2001), thus lowering homocysteine levels.
Selenium. The trace mineral selenium is necessary
for the antioxidant activity of glutathione, which is converted from
homocysteine. Selenium deficiency has been shown to increase oxidative
damage in animals. By boosting selenium levels, you can raise your
level of glutathione and help lower your homocysteine level (Devlin TM
2001).
N-acetylcysteine. Consuming N-acetylcysteine may
reduce homocysteine levels by encouraging the production of cysteine,
which is critical to the conversion of homocysteine to glutathione. By
increasing the production of cysteine, people with depression may be
able to boost the amount of homocysteine converted into glutathione.
Cysteine. Like N-acetylcysteine, cysteine may
prevent the release of stored homocysteine into the bloodstream. Life
Extension Foundation favors maintaining an adequate level of cysteine
to preserve normal glutathione levels.
Not all the homocysteine created is released directly into the
bloodstream as free homocysteine. In fact, less than 1 percent of the
homocysteine in the blood is free. The majority, about 98 to 99
percent, is bound to proteins in the blood and considered stored. This
store of homocysteine may be released in response to decreased
methylation or oxidative damage or in response to other influences. The
following nutrients have been shown to inhibit the release of
homocysteine:
Creatine. Somewhere between 50 and 90 percent of
the SAMe required by the body goes into the production of creatine
(Silveri MM et al 2003; Devlin TM 2001; Stead LM et al 2001; Lee H et
al 1998; Finkelstein JD et al 1984). Supplementation with creatine
diminishes the need for SAMe and reduces the formation of homocysteine
and the need for homocysteine remethylation. In animal studies,
supplementation with creatine for two weeks reduced homocysteine levels
by 25 percent (Stead LM et al 2001).
Choline-producing nutrients. SAMe is involved in
the production of choline. If you take choline-producing nutrients,
your body produces less SAMe, which reduces the amount of homocysteine
needed, thus helping to maintain normal levels. Choline-producing
nutrients include cytidine diphosphate choline, lecithin,
alpha-glycerylphosphorylcholine, and choline chloride.
A prescription alternative to folic acid. For
people who do not achieve results with supplements, a new drug called
Metafolin® was recently introduced. The drug is a natural folate (folic
acid is a synthetic folate) and is readily available to the body.
According to its manufacturer, Metafolin® may be superior to folic acid
supplementation because it does not bear the risk of unmodified folic
acid accumulation and is less likely to mask signs of a vitamin B12
deficiency.
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