Articles

Depression

Introduction

Depression has been part of the human condition since antiquity. Hippocrates is generally credited with the first description of an affective disorder and is thought to have coined the term "melancholia," literally translated as "black bile." (1)

Although life is filled with unexpected events such as the death of a loved one, loss of a job, major illness, or other catastrophic events, not everybody becomes depressed. Most individuals suffer only transient, dysphoric feelings and find ways to adjust to life’s challenges. However, there are certain individuals who, when faced with such psychosocial stressors, experience a major depressive episode.

Depression has been classified as a mood disorder or affective disorder. Mood is defined as a pervasive and sustained emotion that, in the extreme, markedly affects a person’s perception of the world and ability to adequately function in society. (2) Mood disorders are among the most common encountered in clinical practice and are divided into depressive disorders and bipolar disorders.

Depression is a common disorder that affects approximately 5 percent of the population at any given time, and about 30 percent of adults will suffer from depression over a lifetime. (3) Commonly thought of as a disorder of young to middle adulthood, with an average age of onset in the late 20's, depression is also recognized as a common psychiatric illness in the elderly. (4) Women are two to three times more likely to suffer from depression than men. (5) Rates of depression increase with the presence of concomitant medical illnesses, including myocardial infarction survivors (40-65 percent), diabetic patients (8.4–32.4 percent), cancer patients (25 percent), and stroke survivors (10-27 percent). (6)

There are over 187 million adults in the United States – and about 19 million of these people will experience a depressive episode in any given year, making depression the most common psychiatric disorder encountered in general medical practice. (7) In 1990, depressive disorders cost the U.S. economy approximately 44 billion dollars, and of this, almost $12.4 billion was spent on diagnosis and treatment. (8)

Mood disorders, depression, and anxiety are common illnesses in our society. Lost work time, family conflicts, personal strife, and other consequences of the disease can eventually lead to complete disruption of one’s life. Depression and mood disorders have become increasingly recognized as common, yet under-diagnosed and under-treated conditions. (9)

The etiology of depressive disorders is too complex to be totally explained by a single social, biologic, or developmental theory. Several factors seem to work together to cause or precipitate depressive disorders. Heredity does seem to have a role, as studies have shown. Depressive disorders and suicide tend to cluster in families, and first-degree relatives of patients with depression are one and one half to three times more likely to develop depression than normal controls. (10) The symptoms reported by patients with major depression consistently reflect changes in the brain monoamine neurotransmitters, specifically norepinephrine, serotonin, and dopamine. (11)

Depleted serotonin due to prolonged stress, adrenal exhaustion, hypothyroidism, heavy metal toxicity, and "leaky gut" syndrome with subsequent food intolerance, and deficiencies in B12, folic acid, and amino acids, are some of the secondary factors contributing to depressive states.

Statistic

World Health Organization, 2002.

  • Currently 121 million people suffer from depression and the burden of depressive illness is rising.
  • The world over, twice as many women suffer from depression as men.

Mental Health foundation of New Zealand, 2007.

  • One person in every eight (12.6% of the population) will have a Major Depressive Episode in their lifetime.
  • One in five females (19.4% of the female population) and one in ten males (10% of the male population) are likely to experience a depressive disorder.

National Institute of Mental Health, 1999.

    19 million people in the US suffer from depression at one time each year. 1 in 10 adults suffer from depression each year. 2 million of the 34 million Americans age 65 and older suffer from depression. Treatments alleviate 80% of the symptoms of depression. Women experience depression roughly at twice the rate as men. This ratio exists regardless of racial and ethnic background or economic status.

Signs and Symptoms

[span class=alert]The following list does not insure the presence of this health condition. Please see the text and your healthcare professional for more information.[/span]

Currently, the criteria listed in the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, published by the American Psychiatric Association in 1994 are used to diagnose individuals with depressive disorders. Criteria for a major depressive episode include:

  • Five (or more) of the following symptoms have been present during the same 2-week period and represent a change from previous functioning; at least one of the symptoms is either depressed mood or loss of interest or pleasure.
    1. Depressed mood most of the day, nearly every day.
    2. Markedly diminished interest in pleasure in all, or almost all, activities.
    3. Significant weight loss (not dieting) or weight gain, or increase or decrease in appetite nearly every day.
    4. Insomnia or hypersomnia nearly every day.
    5. Observable psychomotor retardation or agitation nearly every day.
    6. Fatigue or loss of energy nearly every day.
    7. Feelings of worthlessness or excessive or inappropriate guilt (may be delusional) nearly every day.
    8. Diminished ability to think or concentrate, or indecisiveness.
    9. Recurrent thoughts of death, recurrent suicidal ideation without a specific plan, or a suicide attempt or specific suicide plan.
  • The symptoms cause clinically significant distress or impairment in social, occupational, or other important areas of functioning.
  • The symptoms are not due to the direct psychologic effects of a substance or general medical condition.

Treatment Options

Conventional

The goals of treatment include reducing the symptoms of depression and facilitate the patient’s return to functioning at the level where they were prior to the onset of illness. Usually the treatment includes psychotherapy and the use of pharmacologic agents. The most commonly used medications for uncomplicated depression are the tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors, (SSRIs). If a patient is refractory to the actions of one agent, therapy is often switched to the other. Of the tricyclic antidepressants, amitriptyline and imipramine are the most extensively studied and used. All TCAs potentiate the activity of norepinephrine and serotonin by blocking their re-uptake. Because TCAs affect other receptor systems, anticholinergic, neurologic, and cardiovascular adverse events are frequently reported. (12) SSRIs were developed from the perceived need for improved efficacy and adverse effects profile compared with traditional TCAs. Patients who fail to respond to TCAs often respond to an SSRI, and visa versa.

If a patient is unresponsive to either agent, others are considered, including buproprion, which blocks reuptake of dopamine, mirtazapine, a tetracyclic antidepressant with mixed serotonin/norepinephrine effects, or a triazolopyridine (trazodone or nefazodone), which has a dual action as a serotonin antagonist and also a re-uptake inhibitor.

Monoamine oxidase inhibitors (phenelzine, tranylcypromine) are used in cases of atypical depression. Clinical features of atypical depression that predict preferential response to MAOIs include mood reactivity, irritability, hypersomnia, hyperphagia, psychomotor agitation, and hypersensitivity to rejection. (13)

Nutritional Supplementation


S-Adenosylmethionine (SAMe)

S-adenosyl methionine (SAMe) is one of the most studied non-drug antidepressants available today. SAMe is a naturally occurring substance synthesized in the body from the amino acid methionine. It is critical for the synthesis of neurotransmitters.

When Italian researchers were testing SAMe as a treatment for schizophrenia in the 1970's, they discovered its antidepressant effects, setting in motion clinical studies. A recent meta-analysis concluded, "The efficacy of SAMe in treating depressive syndromes and disorders is superior with that of placebo and comparable to that of standard tricyclic antidepressants. Since SAMe is a naturally occurring compound with relatively few side effects, it is a potentially important treatment for depression." (14) Several studies report that SAMe is more effective than tricyclics. (15) , (16) , (17)

The results of clinical trials highlights another benefit when SAMe is used as an antidepressant agent, which is the fact that it provides a rapid therapeutic response. (18) The excitement surrounding SAMe’s effectiveness as a natural antidepressant is balanced by the fact that it is a relatively costly supplement, if the therapeutic dosage is maintained.


5-Hydroxytryptophan (5-HTP)

5-hydroxytryptophan (5-HTP) and tryptophan are the precursors for serotonin. Tryptophan is an essential amino acid that the body cannot manufacturer. Tryptophan is converted into 5-HTP, which in turn is converted into serotonin. (19) There is ample evidence that tryptophan depletion causes reduced synthesis of serotonin, which results in depression and other mood disorders. (20)

In 1989, the FDA removed tryptophan from the market due to some contaminated batches that caused a number of deaths. It is now available by prescription through compounding pharmacies, and it is also used in TPN feeding and in infant formulas. However, tryptophan is still not available to the general public as a nutritional supplement. Without tryptophan on the market, 5-HTP has entered into the public’s awareness as an effective substitute as a natural therapy for anxiety, depression, and sleep disorders. Either substance can be used to enhance serotonin synthesis in the brain. (21) It is now recognized that 5-HTP is more effective at elevating serotonin levels than tryptophan for the following reasons.

    Intestinal absorption of 5-HTP does not require the presence of a transport molecule, and is not affected by the presence of other amino acids; therefore it may be taken with meals without reducing its effectiveness. Unlike tryptophan, 5-HTP cannot be shunted into niacin or protein production. Therapeutic use of 5-HTP bypasses the conversion of tryptophan into 5-HTP by the enzyme tryptophan hydroxylase, which is the rate-limiting step in the synthesis of serotonin. The 5-HTP is well absorbed from an oral dose, with about 70 percent ending up in the bloodstream. It easily crosses the blood brain barrier and effectively increases central nervous system (CNS) synthesis of serotonin. (22)

The scientific literature on tryptophan’s effectiveness as an antidepressant agent is mixed. However, it appears that there are certain types of depressed patients who respond well to tryptophan therapy. Scientific studies have reported the usefulness of using tryptophan supplementation for the treatment of mild forms of depression. (23) , (24) , (25)

5-HTP has been compared to antidepressant drugs in several clinical trials. Several studies have reported 5-HTP’s antidepressant activity to be equal to tricyclic antidepressants. A multicenter trial in Switzerland reported that 5-HTP alleviated depression more effectively than Luvox. (26) , (27) In Europe, 5-HTP is frequently taken along with a drug named carbidopa, which prevents 5-HTP from being converted to serotonin in the body. This allows more 5-HTP to cross the blood brain barrier and be converted to serotonin in the brain. Using carbidopa with 5-HTP is somewhat controversial because studies report that 5-HTP is more effective and has fewer side effects when taken alone. (28)


Phenylalanine, Tyrosine

Phenylalanine and tyrosine are the precursors to the neurotransmitters dopamine, norepinephrine, and epinephrine, which all influence and regulate mental and emotional states.

Antidepressant activity has been reported in studies using D-phenylalanine or with a mixture of both isomers called DL-phenylalanine (DLPA). Several studies have reported results equal to or better than tricyclic antidepressants without side effects. (29) , (30) People usually respond within two to four weeks, and in one study, severely depressed patients responded well. (31)

Tyrosine is synthesized from phenylalanine and thus, it is not an essential amino acid. However, like phenylalanine, tyrosine is also intimately involved in the synthesis of dopamine, epinephrine, and norepinephrine. Therefore, the benefits and effects of tyrosine are similar to those reported for phenylalanine. Although several small trials with depressed patients have reported impressive results, (32) , (33) no large well-controlled studies on tyrosine and depression have been conducted to date.

Suggested dosages for tyrosine start at 500mg, three times daily and can go up to 6 grams per day. As with phenylalanine, people with high blood pressure should only use it under close medical supervision, and it is contraindicated for those with PKU and melanoma.


Dehydroepiandrosterone (DHEA)

Dehydroepiandrosterone (DHEA), when given to a small group of six depressed middle-aged and elderly patients at a dosage of 30-90 mg/day for four weeks, resulted in improvements in both depression and memory performance. (34) In a double-blind trial with 22 patients suffering from major depression, DHEA provided a significant improvement in depressive symptoms. (35) DHEA appears to be safe and without significant side effects; however, long-term human trials have not been conducted. Therapy with DHEA is contraindicated in individuals with a history of prostate or breast cancer. Dosing is best monitored through physiologic measurements of DHEA.


Omega-3 Fatty Acids

Studies report that the a ratio of low omega-3 to high omega-6 fats correlates positively with clinical symptoms of depression. (36) , (37) The quantity and ratio of omega-3 to omega-6 is critical because they are the precursors to the prostaglandins, which are a group of hormone-like substances that regulate many important aspects of biological function throughout the body. In a book titled Omega-3 Oils, Donald O. Rudin, M.D. reports that giving patients omega-3 supplements often improves mood and relieves depression within one to two weeks. (38)

A randomized, double-blind placebo controlled trial evaluated the antidepressant effects of ethyl-eicosapentaenoate in 70 patients using an adequate dose of a standard antidepressant yet continuing to experience depression. Using three different depression rating scales, the group taking 1gram/day (g/d) of ethyl-eicosapentaenoate had significantly better outcomes than placebo on all three rating scales. The 2g/d and 4g/d, at best, displayed nonsignificant trends toward improvement. (39)

Experimental evidence suggests that only a small percentage of omega-3 gets converted into its longer chain metabolites EPA and DHA. (40) Because of this, some people with depression should consider taking fish oil capsules, which contain a mixture of EPA and DHA. Individuals are encouraged to take at least 400 IU of vitamin E daily when consuming fatty acid nutritional supplements.


Vitamin B6

Vitamin B6 is required for the conversion of tryptophan to serotonin. Therefore, a deficiency of vitamin B6 may result in symptoms of anxiety and depression, due to inhibition of serotonin synthesis. (41) Numerous drugs have been known to deplete vitamin B6, which could then lead to depression.

Oral contraceptives are known to deplete vitamin B6, which may cause depression in susceptible women. In one particular study, administration of 40mg of vitamin B6 daily restored normal biochemical values and also relieved the clinical symptoms in the vitamin B6 deficient women taking oral contraceptive. (42) Other important categories of drugs that may deplete vitamin B6 include corticosteroids, theophylline-containing medications, hydralazine-containing vasodilators, loop diuretics, and estrogen replacement therapy medications. (43)


Vitamin B12

Vitamin B12 deficiency can result in depression, and this is a condition that occurs much more frequently in the elderly. (44) , (45) A Norwegian mental hospital conducted a test in which every patient over 30 years old that was admitted during a one-year period underwent evaluation for vitamin B12 status. The results indicated that the percentage of mental patients with below normal levels of vitamin B12 was 30 times higher than in the normal population in that area. (46) It is important to realize that a vitamin B12 deficiency may cause depression in the absence of anemia. (47)


Folic Acid

According to doctors from the Department of Psychiatry at Harvard Medical School, depressive symptoms are the most common neuropsychiatric manifestation of folate deficiency. Low serum folate levels have been found in 15-38% of adults diagnosed with depression. (48) In one double-blind placebo-controlled study, 41 patients with major depression who had depressed red cell folate levels were treated with methylfolate (15 mg/day) or a placebo. At both three and six months, patients exhibited substantial improvements in clinical outcome scores compared to the placebo controls allowing the authors to determine that folate supplementation might enhance recovery from psychiatric illness. (49) , (50)

Herbal Supplementation


St. John's Wort

St. John’s wort has gained a great deal of attention for its use in minor depression. Its popularity has stemmed from its extensive use by physicians in Europe as an agent of choice in the treatment of mild to moderate depression. There are a variety of studies that are claimed to support the use of St. John’s wort in treating depression. (51) , (52) , (53) Studies with St. John’s wort have centered around the use of a 0.3% hypericin content standardized extract at a dose of 300mg, three times a day. It is viewed as safe and effective in Europe, and its monograph is part of the Commission E Monographs for herbal medicines in Europe. St. John’s wort has several possible effects on body chemistry, including: the inhibition of cortisol secretion and the blocking of catabolic hormones, such as interleukin 6 (IL-6); (54) the inhibition of the breakdown of several central nervous system neurotransmitters, including serotonin (it may have mild MAO-inhibiting activity; this has not been clearly defined and cannot explain all the activity of St. John’s wort; researchers do not consider this to be its major mechanism of action); (55) , (56) , (57) amplification and improvement in the signal produced by serotonin once it binds to its receptor sites in the brain; (58) , (59) and contains the chemical melatonin (approximately 4.39 mcg/gm), which may also contribute to the antidepressant effects of the plant. (60)

Although the constituent hypericin was originally thought to have the antidepressant effects seen when using St. John’s wort, recent research has reported that the constituents pseudo-hypericin and hyperforin may enhance serotonin, catecholamines, and glutamine levels in the brain. (61)

Literature has reported cytochrome P-450 enzyme-inducing activity of St. John’s wort in human studies. Interactions between St. John’s wort and anticoagulants, indinavir, cyclosporin, digoxin, ethinyl estradiol/desogestrel, and theophylline have occurred. (62) The mechanism of action was believed to be liver enzyme induction and subsequent alterations of drug levels by the herb. Also, several reports have suggested that concurrent use of St. John’s wort and SSRIs may result in "serotonin syndrome", including sweating, tremor, confusion, flushing, and agitation. (63) , (64) Use St. John’s wort with caution if individuals are on these medications.


Ginkgo

Ginkgo is among the oldest living species on earth and has been used extensively as a medicinal agent worldwide for centuries. It is the most frequently prescribed medicinal herb in Europe. The most dramatic benefits are reported in improving circulation in the elderly. (65) , (66) This can lead to enhanced memory, delaying the onset of Alzheimer's, (67) and reducing senile dementia, (68) tinnitus, (69) and vertigo. (70) Ginkgo’s memory-enhancing effects are reported in younger populations as well. The main active components of ginkgo are the flavoglycosides. These compounds act as free radical scavengers or antioxidants. (71) Ginkgo is also reported to inhibit platelet activating factor (PAF), which could reduce the adhesive nature of platelets, possibly through competitive binding. Ginkgo may foster vasodilation by stimulating endothelium releasing factor and prostacyclin. (72) It may also stimulate venous tone and improve the clearance of homotoxins during ischemic episodes. (73) Gingko reportedly acts as a tonic for the circulatory system. It may increase cerebral brain flow, and therefore, improve delivery of nutrients to the brain, enhancing elimination of the byproducts of cell metabolism and oxygenating the tissues. (74) Ginkgo may normalize acetylcholine receptors and improve cholinergic function. (75)

Ginkgo has also been used to treat impotence, especially when associated with antidepressant therapy. (76) , (77) Ginkgo has traditionally been used as an adjunctive agent in resistant depression, often used in combination with St. John’s wort. (78)


Rhodiola

Rhodiola has long been used in traditional folk medicine in China, Serbia, and the Carpathian Mountains of the Ukraine. In the former Soviet Union, it has long been used as an adaptogen, decreasing fatigue and increasing the body’s natural resistance to various stresses. Rhodiola seems to enhance the body's physical and mental work capacity and productivity, working to strengthen the nervous system, fight depression, enhance immunity, elevate the capacity for exercise, enhance memorization, improve energy levels, and possibly prolong the life span. (79) The effect of alcohol-aqueous extract from rhodiola roots on the processes of learning and memory was studied in rats. (80) For the treatment of depression extracts of rhodiola, namely rosavin and salidroside, in animal studies seem to enhance the transport of serotonin precursors, tryptophan, and 5-hydroxytryptophan into the brain and decrease the action of COMT (catechol-O-methyltransferase), an enzyme that degrades serotonin. (81) Russian scientists have used Rhodiola alone or in combination with antidepressants to enhance mental state and decrease the symptoms of SAD or Seasonal Affective Disorder common to Northern European countries. Additional studies need to be performed to verify its effectiveness for this particular function.

Homeopathic

Aurum metallicum

Typical Dosage: 6X or 6C, 30X or 30CSadness; Despair; Disgusted with life; Constant self-reproach; Intolerant to noise; Better from music; Tendency to be irritable and angry

Kali bromatum

Typical Dosage: 6X or 6C, 30X or 30CSadness with an uncontrollable desire to cry; Restlessness (especially of the hands); Insomnia with nightmares; Memory loss; Indifference to life

Sepia

Typical Dosage: 6X or 6C, 30X or 30CPessimistic; Indifferent to everything and everyone; Afraid of being alone; Sadness; Aversion to sex

Acupuncture & Acupressure

Yang treated 18 cases of depression with electric acupuncture. The acupoints Baihui (Du 20) and Yingtang (Extra 1) were treated for one hour daily. A comparison group of 14 cases was treated with amitriptyline. The results: of the treatment group, 10 cases were resolved, 4 significantly improved, 2 improved, and 2 did not respond to the treatment; 10 cases of comparison group significantly improved. The comparison group needed a small dose of anti-depression medication to sustain its therapeutic effect, while the treatment group needed none. (82)

Shang, et al. treated 30 cases of post-apoplectic depression with head acupuncture. 50-milllimeter filiform acupuncture needles were used to puncture the midfrontal, vertex, frontal, posterior and anterior temporal lines for a depth of 15-25 millimeters. The universal reinforcing-reducing maneuvering method was used, and the needles were twirled at 200 rotations/minute, and retained for 30 minutes. One unit of treatment consisted of 30 daily sessions. The results: after one unit of treatment, 12 cases were resolved, 9 significantly improved, 5 improved, 4 did not respond to the treatment, with a total effective rate of 86.7%. (83)

Song, et al. treated 29 cases of post-cerebral apoplectic depression with cutaneous head acupuncture, and compared the results with those of a group of randomly selected 28 cases treated with Western medication. The treatment group had a total effective rate of 89.6%, while the comparison group had one of 71.4%; the difference was significant (P

Traditional Chinese Medicine

Depression

Extensive information regarding the treatment of this health condition using Traditional Chinese Medicine is available through the link above.

Diet & Lifestyle

Eliminate sugar, caffeine, and alcohol.

Identify and eliminate food allergies.

Exercise.

Light therapy.

Stress reduction can take form in a variety of ways. Some of the more structured forms include; counseling, tai chi, yoga, meditation, deep breathing.

Clinical Lab Assessment

Some of the following laboratory testing can provide information necessary for diagnosis and treatment. In addition, the tests listed may also give insight to functional metabolism and functional nutrient status in the body.

Thyroid Profile

It is well known that hypothyroid function is associated with depression.

Organic Acids

Organic acids analysis is a useful method for measurement of biochemical intermediates in urine. Deficiencies of biotin, (84) , (85) folic acid, (86) vitamins B1, (87) B2, (88) B6, (89) B12, (90) , (91) and C (92) have all been implicated in depression. Organic acids analysis is a cost-effective means of evaluating functional vitamin status for these nutrients. A subset of organic acids, the dysbiosis markers, may provide useful information regarding gastrointestinal pathogens that can contribute to compromise of neurologic function resulting in depression.

Amino Acids

Deficiencies or imbalances in amino acids can indicate fundamental reasons for numerous disorders. Amino acid malabsorption syndrome or imbalanced amino patterns reflect abnormal organ and glandular processes that have critical bearing on optimal function. Imbalances in tyrosine, phenylalanine, tryptophan, methionine, and other amino acids have been associated with depression.

Mineral Analysis

The evaluation of essential and/or toxic elements can be of use in the evaluation of many clinical conditions. Essential mineral imbalances can affect nearly any tissue and organ resulting in a myriad of disorders. Trace element deficiencies can disproportionately affect enzyme systems that are used in regulatory substrates, resulting in amplified disease conditions. Imbalances in calcium, copper, iron, lithium, and magnesium have all been associated with depression.

Allergy and Food Sensitivity Response Assessment

Allergic disorders are common among depressed patients. (93) Direct correlation of impaired digestion or food allergic response is controversial, though some case studies manifest improvements on food elimination diets.

Fatty Acids

Imbalances in fatty acid levels have been associated with depression. (94)

Glucose

Blood glucose levels vary in response to food intake, stress, physical exertion, and various disorders. Elevations of serum glucose should lead to confirmatory testing such as fasting insulin, serum phosphorus, magnesium, hemoglobin A1c, and/or fructosamine.

Clinical Notes

Check hormones through lab analysis, including cortisol and DHEA; assess potential heavy metal toxicity and nutrient deficiencies.

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