Lifting Depression With "Bio-identical" Mood Enhancers (Part 2)
by Leslie J. Farer

In Part I of this article, we discussed the growing global incidence of depression and the often limited success of conventional drugs in treating it. Despite the ever-expanding pharmaceutical pipeline for antidepressant medications, with their various “new and improved” mechanisms of action, they are potentially toxic, side effect laden and ineffective in up to one third of those who take them. (1) Clearly, there is a need for therapies which provide symptom relief without compromising tolerability and safety. Fortunately, a sizable body of clinical research has demonstrated the efficacy of certain physiologically occurring (i.e., “bio-identical”) compounds in treating this disease by normalizing, rather than manipulating, brain chemistry. In addition, these carbon copies of biological substances display a faster onset of action, low toxicity and minimal side effects. Previously we covered SAMe, NADH, 5-HTP and l-tryptophan; here our discussion will focus on acetyl-l-carnitine, DHEA, and the omega-3 fatty acids.

Caution: If you are currently taking an antidepressant, do not stop or alter treatment without physician supervision. If you do not take medications and would like to try one of these supplements, it would be prudent to inform your physician, then take one at a time for a course of four to eight weeks to determine its effect. Dosages listed should be used as guidelines only; consult your health-care professional if you wish to exceed these recommendations.

Acetyl-l-carnitine (ALC)

ALC is the acetylated ester of the amino acid derivative l-carnitine. ALC has shown promise in treating an array of conditions, from Alzheimer’s, diabetic neuropathy, and the diminished cellular energy levels and mitochondrial dysfunction associated with aging, to cognitive impairment and depression. (2,3) Like l-carnitine, ALC shuttles long-chain fatty acids across the inner mitochondrial membrane where they undergo oxidation to produce energy in the form of ATP. What makes ALC unique is its specialized function of donating its acetyl moiety to the synthesis of biologically important compounds including acetyl coenzyme A, a key metabolic intermediate, and acetylcholine, a neurotransmitter involved in memory and learning. ALC easily crosses the blood-brain barrier (2,3) and has been shown to provide neuroprotective and neuroregenerative benefits. (2) ALC’s neurologic and energy generating mechanisms may underlie its reported antidepressive effects.

Research conducted in the late 1980’s and early 1990’s (4,5,6) demonstrated the efficacy and safety of ALC in treating depression in geriatric patients. In one study, administration of 1.5 g/day of ALC counteracted depressive symptoms in 28 patients aged 70 to 80. (5) In another, 60 senile patients, 60 to 80 years old, with dysthymia, a low-grade chronic form of depression, received either 3 g/day of ALC or placebo. ALC-treated patients experienced a significant reduction in symptoms and improvements in “quality of life” compared to those receiving placebo. (6)

A recent larger-scale study that was not restricted to older individuals compared ALC (1 g/day) to the conventional antipsychotic drug amisulpride (50 mg/day) in treating dysthymia in 204 subjects. Patients experienced similar symptom reduction on each regimen, leading researchers to conclude, “The greater tolerability of ALC is of clinical relevance considering the chronicity of dysthymia, which often requires prolonged treatment.” (7)

Dosage: 1 to 3 g daily, in divided doses.

Dehydroepiandrosterone (DHEA)

Most readers are familiar with the multi-faceted benefits of the hormone DHEA, and for many aspiring centenarians, it is a core ingredient in their daily anti-aging regimen.

DHEA and its sulfate metabolite, DHEA sulfate (DHEA-S), are the most plentiful circulating steroid hormones in the human body. (8) Produced primarily in the adrenal glands, DHEA also is considered a neurosteroid due to its synthesis in and action on the brain. Production peaks between 20 to 30 years of age, and then progressively declines with each successive decade. Between ages 50 to 60, DHEA levels have fallen to about 70% of peak values, (9) only to decline even further with advancing years. In fact, serum DHEA-S concentration is an accurate and useful biomarker of aging. Maintaining optimal, youthful DHEA and DHEA-S levels throughout life may be implicated in longevity.

Since the 1980’s several hundred studies have been published on DHEA’s health-promoting benefits, from anticancer, immune-enhancing, general antiaging and neurotropic effects, to treating adrenal insufficiency and alleviating depression. (10,11) Some researchers believe that epidemiological data support a direct relationship between DHEA and DHEA-S levels and positive mood, (11,12) although it may be that the ratio of DHEA (or DHEA-S) to the stress hormone cortisol is a more accurate indicator of emotional state (lower ratios due to decreased DHEA and increased cortisol are thought to correlate with low mood).

In what was reported to be the first demonstration of the effects of DHEA replacement on aging men and women, 30 subjects between the ages of 40 and 70 were administered 50 mg/day of DHEA in a 3 month placebo-controlled trial. In the treated group, the restoration of DHEA and DHEA-S serum levels to those of a young adult was accompanied by an increase in “physical and psychological well-being” in about three quarters of study subjects. (13) This marked effect on demeanor opened the door to other research that would specifically elucidate the role of DHEA in depression.

In 1999, the first double-blind placebo-controlled trial evaluated DHEA as an individual or adjunct treatment in major depression. 22 patients aged 33 to 53, who were either medication-free or on a stabilized dose of a conventional drug, received graduated doses of up to 90 mg/day of DHEA or placebo. The goal of the researchers was to restore DHEA and DHEA-S serum levels to the high end of the physiological range of a 20 to 30 year-old adult. After 6 weeks, half of the DHEA-treated participants (compared with none of the placebo group) experienced at least a 50% decrease in depressive symptoms — an impressive result considering that many of the patients did not respond adequately to conventional antidepressants alone. (11) In a 2005 study, researchers at the National Institute of Mental Health investigated the use of DHEA as a monotherapy in treating a common symptom of aging: mid-life onset depression. 46 medication-free patients between the ages of 45 and 65 received either DHEA (90 mg/day for 3 weeks followed by 450 mg/day for 3 weeks) or placebo. At the end of 6 weeks, a pronounced improvement (50% or greater) in mood rating scales was observed in half of the DHEA-supplemented patients, (14) confirming the outcome of the 1999 study. No additional benefit was observed with the higher 450-mg dose. (Note: The researchers did not present the patients’ serum DHEA and DHEA-S concentrations, which likely reached supra--physiological levels on the higher dose.)

The latest research indicates that DHEA may also benefit the depression that often accompanies, and is secondary to, HIV/AIDS. In an 8-week study, 60% of patients receiving DHEA (100 to 400 mg/day) showed mood improvement, compared with 30% of those receiving placebo. (15)

Just how does DHEA exert its antidepressant action? In part, by metabolism to testosterone and estrogen, both of which may have mood-enhancing effects of their own. (10,11) Also, as mentioned earlier, elevated cortisol and lowered DHEA are implicated in psychiatric and physical diseases, and supplementary DHEA may help restore a more healthy balance between the two hormones. (10,16) In addition, DHEA crosses the blood-brain barrier (10) and is thought to effect GABA, N-methyl-D-aspartic acid, and sigma receptors, as well as serotonin levels. (11)

Caution: DHEA may potentially be metabolized to testosterone and/or estrogen and should be avoided in those with hormone-sensitive tumors (i.e., of the breast, cervix, uterus, or prostate).

Dosage: Optimal dosage varies widely between individuals. A baseline DHEA-S blood test should be performed to determine a suitable starting dose (usually between 10 to 50 mg). Repeat the DHEA-S blood test 3 to 6 weeks after beginning DHEA supplementation and adjust dosage as necessary. Periodic blood monitoring will ensure that your DHEA-S level is within the optimal range for a young adult. Physician supervision is advised.

Omega-3 Fatty Acids

The role of omega-3 fatty acids in promoting cardiovascular health has been well established and emerging research is demonstrating their importance to mental health as well.

Omega-3’s are a subset of the family of essential fatty acids (EFA’s), long- chain polyunsaturated acids derived from marine and vegetable sources. EFA’s are classified as “essential” because they cannot be synthesized in the body and must be obtained from the diet. Important omega-3’s are the parent compound, alpha- linolenic acid (ALA), and its metabolites, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA); they play a critical role in the development and function of the central nervous system. EPA and DHA are derived from cold water oily fish such as salmon, herring and mackerel, and ALA is found in plant sources, including flaxseed, hemp, canola, and walnut oils. (ALA can be metabolized to the longer-chain EPA and DHA, but only to a limited degree — 5 to 15%. (17))

Another group of EFA’s are the omega-6 fatty acids, found in the healthful source evening primrose oil, as well as in less desirable vegetable oils, such as corn and sunflower oils, present in processed foods. Both omega-3 and omega-6 fatty acids are essential; however, metabolites of the omega-6 group are significantly more inflammatory than those of omega-3 (18) and may lead to negative health consequences. Researchers postulate that the dramatic decline in the dietary intake of omega-3’s and the escalating consumption of omega-6’s in the Western world may be at the root of the corresponding rise in psychiatric disorders in the past century! (17, 19) This trend of increasing incidence of depression is not seen in populations with higher rates of fish consumption. (17, 18)

Considering that lipids comprise 60% (17, 18) to 80% (19) of the solid mass of the brain and that more than one third of these lipids are omega-3 fatty acids, (20) one can appreciate their absolute importance to the proper structure and function of the brain. Omega-3’s are a fundamental component of the phospholipid chains making up neuronal membranes; (17, 18, 19) they ensure the fluidity required for optimal neurotransmitter function and cell signaling systems. If unavailable, omega-3’s will be replaced by non-EFA’s, (19) changing the very structure of the phospholipid chains, potentially impeding receptor and neurotransmitter function and negatively impacting mental health. In addition to providing neuronal membrane integrity, omega-3’s inhibit inflammatory immune chemicals (cytokines) implicated in depression, (18) promote adequate blood flow to the brain, (21) and ensure production of the neuro-chemical phosphatidylserine which displays mood-lifting properties of its own. (22)

In one of the first double-blind placebo-controlled studies evaluating omega-3’s as an adjunct treatment for depression, 30 patients with bipolar disorder received either 9.6 g of omega-3 fatty acids per day (6.2 g EPA plus 3.4 g DHA) or placebo (olive oil) in addition to antidepressant medication for 4 months. The omega-3 group experienced considerable symptom improvement with a longer period of remission than the placebo group. (23) In fact, the positive outcome was so pronounced that the study was terminated so that the placebo group could begin omega-3 supplementation.

More recent research has focused on a purified ethyl ester analog of EPA used in conjunction with standard medication. In one trial, 70 patients with persistent depression despite conventional drug therapy received either placebo or ethyl-EPA (1, 2, or 4 g/day) for 12 weeks. Surprisingly, the group receiving the lowest dose of ethyl-EPA, 1 g/day, experienced the greatest improvement in depression, anxiety and sleep disturbances compared with the higher dose or placebo groups. (24) In two related studies, however, a higher dose of ethyl-EPA co-administered with standard medication did result in significant symptom reduction. In one, 1 g/ day of ethyl-EPA was as effective as 2 g in treating bipolar depression in 75 patients. (25) In another, administration of 2 g/day of ethyl-EPA resulted in marked improvement by the third week of treatment in 20 patients with major depression. (26)

What is noteworthy in all of these studies is that cases of persistent depression, unresolved by conventional drugs alone, remarkably improved when omega-3’s were added to patients’ regimens.

Omega-3’s have also been studied as a monotherapy in treating depression and the latest research indicates that they are beneficial in ameliorating depressive symptoms in children, (27) where safety and tolerability are paramount.

Dosage and Use: Due to the presence of heavy metals and toxins in the environment, and therefore in the fish population, it is essential to use a purified EFA product, free of harmful chemicals. Although dosing has varied widely in the reported studies, it appears that 1 to 2 g daily of total omega-3 fatty acids may be taken for general health benefits and that that 1 to 4 g or more may be necessary to resolve depressive symptoms. Take in divided doses with meals.

Caution: Consult your physician before supplementing with omega-3 fatty acids if you are on anticoagulant medications such as Coumadin® (warfarin) or have a tendency to excessive bleeding.

The efficacy, safety, and high tolerability of these bio-identical mood enhancers, used either singly or in conjunction with conventional pharmaceuticals, have been clinically established. Future research will augment our already sizable body of knowledge on these intriguing natural substances, which have as yet to be fully utilized in the arsenal of treatments against depression.

Conclusion

The efficacy, safety, and high tolerability of these bio-identical mood enhancers, used either singly or in conjunction with conventional pharmaceuticals, have been clinically established. Future research will augment our already sizable body of knowledge on these intriguing natural substances, which have as yet to be fully utilized in the arsenal of treatments against depression.

References

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