Affect D

Affect D is an anxiolytic and sedative and may be used for medium to severe depression, bi-polar disorders, acute insomnia, OCD and PTSD. Affect D combines Western therapeutic compounds with traditional Chinese herbs as well as a specific molecular extract from a famous pain herb. Affect D is an all-natural product, which has similar therapeutic effects of well-known pharmaceuticals to treat severe psychological conditions.

Dr. Candace Pert, former National Institute of Health researcher, in her book, "Molecules Of Emotions" explains how emotion-carrying peptides (made from aminos) continually circulate and communicate throughout our brains and bodies. Receptors for these peptides and neurotransmitters are present not only in our brains, but our endocrine systems, spinal cords, and even our immune systems. She says, "What we experience as an emotion or feeling is also a mechanism for activating a particular neuronal circuit - SIMULTANEOUSLY THROUGHOUT THE BRAIN BODY - which generates a behaviour- with all the necessary physiological changes that behaviour would require.

She relates how brain peptides and substances like ACTH are present in many body systems. For example, the immune system networks with the endocrine system and the brain and the nervous systems, all having the proper receptors for getting this information, from carriers called neuro-peptides. She found receptors on immune cells for virtually every peptide or drug identified in the brain. Thanks to this work, our belief that the brain is the seat of our emotions, just flew out the window! Our emotional network exists everywhere throughout our entire bodies. AND is best treated by treating the entire body.

Depression

A common cause of depression is catecholamine deficiency in the brain. Phenylalanine, and Tryptophan are the amino precursors of these catecholamines. In one double-blind study, Phenylalanine proved comparable to the antidepressant drug, Imipramine.

Tryptophan's benefits in loading the brain with serotonin to lift depression are well documented. The Journal of Biological Psychiatry, 1985 describes how abnormal tryptophan and serotonin metabolism can cause impulsive acts of suicide.

Major depressive disorder is very common, with a lifetime prevalence of 17% and a rate almost twice as high in women as in men (16,17). Despite the increasing number of registered antidepressants (20- 25) and the increasing number of people seeking antidepressant treatment, many individuals prove to be refractory, demonstrating nonresponse or partial response after an adequate trial of antidepressants.

Between 19% and 34% of depressed patients still do not respond to acute antidepressant treatment, 29- 46% may fail to achieve and sustain a full remission (18), and between 15% and 50% will have a recurrence of depression despite continuous anti- depressant treatment (19). Registered antidepressants clearly have their limitations, and the importance of other types of treatment is paramount.

In recent years there has been a surge in the popularity of natural or alternative medications. Despite this growing popularity, there is limited evidence for the effectiveness of many of these natural treatments. The terms "natural" and "alternative" in this article refer to medications derived from natural products but not approved by the Food and Drug Administration for their purported indication.

Such treatments have been used for thousands of years. More than 70% of individuals worldwide use some sort of alternative treatment, particularly in Europe and Asia , where many of these treatments originated (21). The United States has followed suit, as evidenced by the growing popularity of natural remedies. Over 50% of Australians seek and obtain non-traditional treatments and visit practitioners of alternative medicine more frequently than they visit primary care physicians (23).

Anxiety

The adrenalin outpouring we experience when we are stressed is the culprit that creates our anxious feelings. That alarm system heightens our mental alertness, and may cause stomach queasiness, sudden sweating, shakiness, and a racing heart.

Vitamin B12

Many studies have been done on the issue of whether B12 deficiency relates to age-related cognitive decline in normal people. Results have been mixed. One of the problems is getting an accurate reading on B12 levels. Blood levels don't necessarily reflect tissue levels. Another problem is that folate deficiency can complicate the picture. A study in people 65+ found that folate levels significantly correlate with cognitive function, but B12 did not. Another study published at the same time (but using a different kind of evaluation) found that supplemental B12 improves cognition, notably, a person's ability to remember words.

Other than anemia, the symptoms of B12 deficiency are rarely documented. Researchers involved in the gastrectomy study at Tufts University took the uncommon step of doing an in-depth analysis of the symptoms of B12 deficiency. They found that lassitude (exhaustion), fatigability (tiring easily), chills (cold hands and feet), numbness in the extremities (no feeling in arm, leg, foot), dizziness, glossitis (painful tongue), leukoplakia (white spots on the tongue) and erectile dysfunction were symptoms of B12 deficiency.

Methylcobalamin is the superior form of Vitamin B12 to use, especially in a formulation that is designed to impact on mood. Methylcobalamin is the only form of vitamin B12 found in the brain and it supports a healthy brain, spinal cord and nervous system, which together are a necessary foundation for optimum mental and emotional health.

Methylcobalamin is essential for the metabolism of nerve tissue and it stimulates the utilization of proteins, fats, and carbohydrates. It is important for the synthesis of DNA and RNA, as well as for production of choline and methionine, a key SAMe component.

Methylcobalamin has been used for many other symptoms including fatigue, nervousness and irritability, insomnia, memory problems, depression, and poor balance.

Adequate methylcobalamin supplementation:

Regulates sleeping patterns and improves daytime alertness

Treats physical and mental fatigue (both a cause and effect of depression)

Ensures optimum cognitive functioning

Balance's mood

Stimulates neuronal regeneration in the brain

Relieves depression, nervousness and irritability

B6 (P5P)

The active form of Vitamin B-6 is Pyridoxal-5- phosphate or P5P, this active form allows for the best absorption, because it is ready to go to work immediately.

It is primarily in the liver that P5P is synthesized from pyridoxine with the help of enzymes this requires Vitamin B2, zinc and magnesium for their activity. P5P is associated with numerous enzymes, many of which are involved in amino acid metabolism. This necessary process produces the neurotransmitters dopamine, nor adrenalin, GABA as well as the hemoglobin in red blood cells.

Many B6 supplements are the inactive pyridoxine HCL form. In some cases supplementation of this form singularly, caused a reversible numbness & tingling of the extremities. In doses as low as 200 mg daily over a 3-year period. This problem was thought to be secondary to the liver's inability to convert this form into the useable P5P form. Using P5P avoids this problem.

It's the P5P our bodies really need to break down and use fats, proteins, and carbohydrates, to make red blood cells and antibodies, to help the digestive and nervous systems function, and to maintain healthy skin. But some folks have trouble-converting pyridoxine into P5P. Those susceptible to a deficiency include some breast-fed infants, elderly persons on a poor diet, and women on estrogen-containing oral contraceptive pills. B6 has recently been found to benefit the autistic and is thought the P5P form may even provide more benefit.

Also, people such as: pregnant and nursing mothers, the elderly, the autistic, and babies at risk of SIDS (Sudden Infant Death Syndrome). P5P is the only form of B6 that the fetus and newborn baby can use. In premature babies, who are more susceptible than full-term babies to SIDS, the use of the pyridoxine form of B6 can result in irreversible central nervous system damage. And lack of P5P can predispose a surviving premature infant to atherosclerosis in later life. In addition, the fact that B6 benefits some persons with Carpal Tunnel Syndrome, and not others, we think may well be traced to the person's ability or inability to make P5P from pyridoxine.

Symptoms of Deficiency:

Depression

Nervousness

Irritability

Slow learning

Increased sensitivity to soun

Impaired calcium utilization

Decreased absorption of copper

Decreased iron statu

Decreased Vitamin B 12 absorption

Low glucose tolerance

Trimethylfolate (Levomefolate calcium)

L-methylfolate is the natural, active form of folate used at the cellular level for DNA reproduction, the cysteine cycle and the regulation of homocysteine among other functions. L-methylfolate is found in leafy green vegetables. Synthetic folic acid works to replicate the action of folate; but must be broken down in a series of metabolic steps in order to become L-methylfolate. Approximately 10% of the general population (heterozygous TT) lack the enzymes needed to receive any benefit from folic acid. Another 40% of the population (homozygous CT) appears to convert only a limited amount of folic acid into L-methylfolate. They cannot fully process supplemental folic acid at RDA or higher dose levels. The remaining populations do not have an MTHFR polymorphism and can fully metabolize folic acid.

Commercial use of L-methylfolate in pharmaceutical products began in Europe in the early part of this decade and has now appeared in the U.S. This approach to folate supplementation has potential to impact prenatal care, homocysteine management and the treatment of depression, dementia and cardiovascular concerns.

Prenatal Care - low folate status has been linked to neural tube defects, recurrent pregnancy loss, low birth weight and a variety of age related high-risk complications of pregnancy.

Depression - folate status has been linked to the performance of SSRI drugs. Many patients have required folate supplementation in order to adequately respond to standard treatment protocol.

Homocysteine Management - elevated homocysteine is frequently linked to the presence of the MTHFR polymorphism.

Dementia - folate status has been linked to the efficacy of neural transmitters and the performance of the blood brain barrier.

Diabetic Neuropathy - folate status has been shown to have a substantial impact upon wound care.

Oral doses of L-methylfolate have been developed in Germany and are now marketed under the brand name Metafolin is a new, coenzymated form of folic acid. Upon absorption, folate is converted into L- methylfolate, which is the predominant form of folate in circulation and is the only type of folate that can cross the blood-brain barrier. Metafolin does not require enzymatic conversion that folic acid does which is difficult for some people. Preliminary research suggests that it is more bioavailable than folic acid.

Zinc

Serious zinc deficiency will affect brain function, creating severe mental problems, including learning and behavioral disorders and an inability to handle stress.

Pregnant animals with zinc deficiency in the last trimester of pregnancy produce off spring with smaller than normal brains and less than half the learning ability. The female offspring born to zinc deficient mothers were violent and aggressive.

Zinc supplementation of deficient 20-year-old students showed a marked difference in scholastic performance after one year, compared to a matched group not receiving zinc.

Zinc and B6

In the past five years research has found a biochemical marker for life-long anxiety symptoms, and have been shocked to see that as many as one- third to one-half of the alcoholics we treat have this genetic, chemical imbalance called pyroluria. A lab test measures levels of kryptopyrroles, a by-product of the blood. High levels of these pyrroles systematically bind with B6 and zinc, preventing the use of these essential nutrients in the brain and body. The result is a myriad of symptoms, including severe inner tension, ongoing anxiety, poor stress control, fearfulness, and sometimes-episodic anger. Often such people have pale skin that easily burns, eyes that are sensitive to light, white flecks/marks on their nails, and stretch marks on their skin. They tire easily, have poor dream recall, and prefer not to eat breakfast, notice upper abdominal pain when stressed, and experience a "stitch" in their side if they run. They have a tendency to become loners as they age. Alcohol provides them with a way to shut off their anxiety, feel sociable, de-stress, and experience a short time when they feel more normal, as if they have found an anxiety cure.

D-Phenylalanine

In a study by E. A. Iumatov et al, stress-protective action was studied of D-phenylalanine, having an ability to decrease destruction of endogenic enkefalins. In the experiments stability of the experimental (receiving D-phenylalanine) and control groups of male rats of August line to emotional stress was compared in conditions of immobilization stress by parameters of animals survival rate, adrenal glands hypertrophy development, involution of thymus, pathologic changes in lungs (abscesses development), ulcero-dystrophic disturbances in stomach, and also the activity and kinetic properties of enzyme tyrosine-hydroxylase in the hypothalamus were determined. It was shown that by several of the mentioned physiological parameters the D- phenylalanine significantly increased the animal's stability to the emotional stress and decreased tyrosinhydroxylase activity, which participates in activation of catecholaminergic processes. 14

In another study by E. Fischer, et al 23 subjects with endogenous depression after a previous unsuccessful treatment with common antidepressive drugs (imipramine-like or MAO inhibitors) dl- or d- phenylalanine was given in daily oral doses of 50 or 100 mg during 15 days. A complete euthymia was obtained in 17 subjects between one and 13 days of treatment. No important adverse reaction was observed. 15

Methionine

While SAMe (S-Adenosyl-l- Methionine) has received a great deal of attention, the pathway of methyl donation is quite a bit more complex. In Affect D we use the component parts to achieve more exacting results (see figure 1). The pathway involves B12, methylfolate and methionine.

MTHFR: methylenetetrahydrofolate reductase; MTHF: methyltetrahydrofolate; 1-Met: methionine; Mat: methionine adeonsyltransferase; Met synthase: methionine synthase; DA: dopamine; 5-HT: serotonin (5-hydroxytryptophan); NE: norepinephrine.

SAMe is synthesized as part of a multistep pathway involving the vitamins folic acid and B-12. The end product then donates methyl groups in the reactions involved in the synthesis of the key neurotransmitters serotonin, norepinephrine, and dopamine. Deficiencies of these neurotransmitters are thought to be involved in the development of depression and other mood disorders.

L-methionine is one of the better studied of the natural remedies. Methionine is a methyl donor and is involved in the synthesis of various neurotransmitters in the brain. A small number of clinical trials with parenteral or oral methionine have shown that, at doses of 200-1600 mg/d, methionine is superior to placebo and is as effective as tricyclic antidepressants in alleviating depression. (5,6).

Hypericum

Extracts of Hypericum perforatum L. ( St John's wort) are now successfully competing for status as a standard antidepressant therapy. Because of this, great effort has been devoted to identifying the active antidepressant compounds in the extract. From a phytochemical point of view, St John's wort is one of the best-investigated medicinal plants. A series of bioactive compounds has been detected in the crude material, namely flavonol derivatives, biflavones, proanthocyanidines, xanthones, phloroglucinols and naphthodianthrones. Although St John's wort has been subjected to extensive scientific studies in the last decade, there are still many open questions about its pharmacology and mechanism of action. Initial biochemical studies reported that St John's wort inhibits the synaptosomal uptake of serotonin, dopamine and noradrenaline (norepinephrine) with approximately equal affinity. However, other in vitro binding assays carried out using St John's wort extract demonstrated significant affinity for adenosine, GABA (A), GABA(B) and glutamate receptors. In vivo St John's wort extract leads to a downregulation of beta- adrenergic receptors and an upregulation of serotonin 5-HT(2) receptors in the rat frontal cortex and causes changes in neurotransmitter concentrations in brain areas that are implicated in depression. In studies using the rat forced swimming test, an animal model of depression, St John's wort extracts induced a significant reduction of immobility. In other experimental models of depression, including acute and chronic forms of escape deficit induced by stressors, St John's wort extract was shown to protect rats from the consequences of unavoidable stress. Recent neuroendocrine studies suggest that St John's wort is involved in the regulation of genes that control hypothalamic-pituitary-adrenal axis function. With regard to the antidepressant effects of St John's wort extract, many of the pharmacological activities appear to be attributable to the naphthodianthrone hypericin, the phloroglucinol derivative hyperforin and several flavonoids. This review integrates new findings of possible mechanisms that may underlie the antidepressant action of St John's wort and its active constituents with a large body of existing literature. 24

L-Tryptophan

Many people find tryptophan to be a safe and reasonably effective sleep aid, probably due to its ability to increase brain levels of serotonin (a calming neurotransmitter when present in moderate levels) and/or melatonin (a sleep-inducing hormone secreted by the pineal gland in response to darkness or low light levels). 25

Clinical research tended to confirm tryptophan's effectiveness as a natural sleep aid and for a growing variety of other conditions typically associated with low serotonin levels or activity in the brain. (Particularly work by Dr. Richard Wurtman at MIT). In particular, tryptophan showed considerable promise as an antidepressant alone, and as an "augmenter" of antidepressant drugs. Other promising indications included relief of chronic pain and reduction of impulsive, violent, manic, addictive, anxiety-related, obsessive, and compulsive behaviours and disorders.

Corydalis (dl-THP)

Scientists have isolated a number of alkaloids from the tuber of corydalis, including corydaline, tetrahydropalmatine (THP), dl-Tetrahydropalmatine (dl- THP), protopine, tetrahydrocoptisine, tetrahydrocolumbamine, and corybulbine.3 Of the full range of 20 alkaloids found in the plant, THP is considered to be the most potent. In laboratory research, it has been shown to exhibit a wide number of pharmacological actions on the central nervous system, including analgesic and sedative effects.4 dl- THP has been found to exhibit a tranquillising action in mice. Scientists have suggested that dl-THP blocks certain receptor sites (e.g., dopamine) in the brain to cause sedation.5

In addition to its central nervous system effects, studies in the laboratory have shown the alkaloids from corydalis also have cardiovascular actions. For example, dl-THP has been shown to both decrease the stickiness of platelets and protect against stroke, 6 as well as lower blood pressure and heart rate in animal studies.7 Additionally, it seems to exert an anti- arrhythmic action on the heart. This was found in a small double blind clinical trial with patients suffering from a specific type of heart arrhythmia (e.g., supra- ventricular premature beat or SVPB). 8 People taking 300-600 mg of dl-THP per day in tablet form had a significantly greater improvement than those taking placebo pills.

Other human clinical trials on dl-THP have shown the ability to fall asleep was improved in people suffering from insomnia after taking 100-200 mg of dl- THP at bedtime. People taking the alkaloid extract.9 reported no drug hangover symptoms such as morning grogginess, dizziness or vertigo

Reports from Chinese researchers also note that 75 mg of THP daily was effective in reducing nerve pain in 78% of the patients tested.10 Painful menstruation (dysmenorrhea), abdominal pain after childbirth, and headache have also been reported to be successfully treated with THP.11

Extracts of the herb may also be useful in the treatment of stomach ulcers. In a large sample of patients with stomach and intestinal ulcers or chronic inflammation of the stomach lining, a 90-120 mg extract of the herb per day (equal to 5-10 grams of the crude herb) was found to improve healing and symptoms in 76% of the patients.12

In another study involving rats in a maze, dl-THP was found to significantly reduce anxiety. Their behaviour and muscle tension were notably changed from control. 13

On the basis of the evidence that vesicular zinc may be essential to the functions of the amygdala, the movement and action of actively functioning zinc in synapses in the amygdala of rats were studied using in vivo microdialysis. The increase of 65Zn release into the amygdalar extracellular space during stimulation with high K+ was inhibited by the addition of 1 μM tetrodotoxin. High-K+-induced 65Zn release was not observed in the substantia nigra, in which zinc-containing glutamatergic neuron terminals are assumed not to exist. The amount of 65Zn released into the amygdalar extracellular space during stimulation with high K+ was correlated with that of glutamate. These results suggest that zinc may be concurrently released with glutamate from the neuron terminals in the amygdala and that zinc may cooperate with glutamate in excitatory neurotransmission. When the amygdala was perfused with 10 μM calcium-ethylenediamine tetraacetic acid (CaEDTA) to chelate zinc in the extracellular space, the levels of glutamate in the extracellular space were not appreciably influenced, whereas those of γ-aminobutyric acid (GABA) were remarkably increased. It is likely that vesicular zinc modulates GABA release in the amygdala. The modulation of GABAergic neuron activity by zinc may be important for the functions of the amygdala.

References

Zhu YP. Chinese Materia Media: Chemistry, Pharmacology, and Applications. Australia : Harwood Academic Publishers, 1998, 445-8.

Bensky D, Gamble A, Kaptchuk T. Chinese Herbal Medicine Materia Medica. Vista , CA : Eastland Press, 1993, 270.

Hsu HY. Oriental Materia Medica: A Concise Guide. Long Beach , CA : Oriental Healing Arts Institute, 1986, 448-50.

Zhu YP. Chinese Materia Media: Chemistry, Pharmacology, and Applications. Australia : Harwood Academic Publishers, 1998, 445-8.

Zhu YP. Chinese Materia Media: Chemistry, Pharmacology, and Applications. Australia : Harwood Academic Publishers, 1998, 445-8.

Xing JF, Wang MN , Ma XY, et al. Effects of dl- tetrahydropalmatine on rabbit platelet aggregation and experimental thrombosis in rats. Chin Pharm Bull 1997;13:258-60.

Lin MT, Chueh FY, Hsieh MT , et al. Antihypertensive effects of dl-tetrahydropalmatine: an active principle isolated from corydalis. Clin Exper Pharm Physiol 1996;23:738-42.

Xiaolin N, Zhenhua H, Xin M, et al. Clinical and experimental study of dl-tetrahydropalmatine effect in the treatment of supraventricular arrhythmia. J Xi'An Med Univ 1998;10:150-3.

Chang HM, But PPH. Pharmacology and Applications of Chinese Materia Medica vol 1. Singapore : World Scientific Inc., 1986, 521.

Lin DZ, Fang YS. Modern Study and Application of Materia Medica. Hong Kong: China Ocean Press, 1990, 323-5.

11.Zhu YP. Chinese Materia Media: Chemistry, Pharmacology, and Applications. Australia : Harwood Academic Publishers, 1998, 445-8.

Chang HM, But PPH. Pharmacology and Applications of Chinese Materia Medica vol 1. Singapore : World Scientific Inc., 1986, 521. Prog Neuropsychopharmacol Biol Psychiatry (2003) 27: 775-9:Pincus HA, Pettit AR. The societal costs of chronic major depression. J Clin Psychiatry 2001;62 (suppl):5-9.

Kendler KS , Thornton LM, Prescott CA. Gender differences in the rates of exposure to stressful life events and sensitivity to their depressogenic effects. Am J Psychiatry 2001;158:587-93.

Fava M, Kaji K. Continuation and maintenance treatments of major depressive disorder. Psychiatr Ann 1994;24:281-90.

Eisenberg DM, Kessler RC, Foster C, Norlock FE, Calkins DR, Delbanco TL. Unconventional medicine in the United States : prevalence, costs, and patterns of use. N Engl J Med 1993;328: 246-52.

Mischoulon D,Rosenbaum JF. The use of natural medications in psychiatry. A commentary. Harv Rev Psychiatry 1999;6:279-83.

Krippner S. A cross cultural comparison of four healing models. Altern Ther Health Med 1995;1:21-9.1

National Institutes of Health, Office of Alternative Medicine, Practice and Policy Guidelines Panel. Clinical practice guidelines in complementary and alternative medicine. An analysis of opportunities and obstacles. Arch Fam Med 1997;6:149-54.CNS Drugs. 2003;17(8):539-62.

Wurtman RJ, Shoemaker WJ, Larin F (1968). "Mechanism of the daily rhythm in hepatic tyrosine transaminase activity: role of dietary tryptophan". Proc Natl Acad Sci U S A 59 (3): 800- 7. PMID 4384464.

Minami A, Takeda A, Yamaide R & Oku N. Relationship between zinc and neurotransmitters released into the amygdalar extracellular space. Brain Research. Volume 936, Issues 1-2, 17 May 2002, Pp. 91-4. doi:10.1016/S0006-8993(02)02499-X

Homocysteine, folate, methylation, and monoamine metabolism in depression.

Bottiglieri T, Laundy M, Crellin R, Toone BK, Carney MW, Reynolds EH. J Neurol Neurosurg Psychiatry. 2000 Aug;69(2):228-32. 

Objectives: Previous studies suggest that folate deficiency may occur in up to one third of patients with severe depression, and that treatment with the vitamin may enhance recovery of the mental state. There are, however, difficulties in interpreting serum and red cell folate assays in some patients, and it has been suggested that total plasma homocysteine is a more sensitive measure of functional folate (and vitamin B12) deficiency. Other studies suggest a link between folate deficiency and impaired metabolism of serotonin, dopamine, and noradrenaline (norepinephrine), which have been implicated in mood disorders. A study of homocysteine, folate, and monoamine metabolism has, therefore, been undertaken in patients with severe depression.

Methods: In 46 inpatients with severe DSM III depression, blood counts, serum and red cell folate, serum vitamin B12, total plasma homocysteine, and, in 28 patients, CSF folate, S-adenosylmethionine, and the monoamine neurotransmitter metabolites 5HIAA, HVA, and MHPG were examined. Two control groups comprised 18 healthy volunteers and 20 patients with neurological disorders, the second group undergoing CSF examination for diagnostic purposes.

Results: Twenty four depressed patients (52%) had raised total plasma homocysteine. Depressed patients with raised total plasma homocysteine had significant lowering of serum, red cell, and CSF folate, CSF S-adenosylmethionine and all three CSF monoamine metabolites. Total plasma homocysteine was significantly negatively correlated with red cell folate in depressed patients, but not controls.

Conclusions: Utilising total plasma homocysteine as a sensitive measure of functional folate deficiency, a biological subgroup of depression with folate deficiency, impaired methylation, and monoamine neurotransmitter metabolism has been identified. Detection of this subgroup, which will not be achieved by routine blood counts, is important in view of the potential benefit of vitamin replacement.

Research: Therapeutic effect of “Affect D” for depressive symptoms.

By Dr Daniel Weber, PhD MSc & Dr James Laporta MBChB(UCT), DMH(SA)

Depression is one of the most common reasons for using complementary and alternative therapies.1 Depression is one of the most frequent psychological problems encountered in medical practice. While the exact aetiology of depression is unknown, numerous factors appear to contribute. These include genetics, life/event sensitisation and biochemical changes. Nutrition, however, can play a key role, both in the onset, severity, and duration of depression, including daily mood swings.2 Causal influence has frequently been assumed in studies documenting a positive association between physical illness and psychological distress. A psycho-somatic link exists between mood disorder and physical well being including nutrition.3

Complementary and alternative therapies are used more than conventional therapies by people with self-defined anxiety attacks and severe depression in a study by Ronald C. Kessler, et al (2001)4. Most patients visiting conventional mental health providers for these problems also use complementary and alternative therapies. Increasing clinical evidence for the effectiveness of herbal antidepressants has led to investigations at the molecular level. A study by Pennington et al (2009)5 investigated similarities in protein expression between clomipramine, St John’s wort and Chinese herbal formulas, often used in mood disorder treatment. The study provides preliminary evidence for multiple common molecular targets between conventional and alternative antidepressants, which appear to collectively affect neuronal plasticity.

Our Affect D formula contains a combination of ingredients with powerful anti-depressant properties and certain analgesic, anxiolytic and mild sedative effects. This document will serve to support the anti-depressant therapeutic value of Affect D through research on two of the main ingredients- St John’s wort & 5-hydroxytryptophan (5HTP). We will also mention further traditional Chinese, Ayurvedic, and other herbal ingredients that support Affect D’s antidepressant safety and efficacy through traditional and historical use, and where applicable, in vivo and in vitro studies on pharmacological effect and mechanism of action.

A clinical look at Depression: Depression is a common mental health disorder. Depressive symptoms include a low mood and loss of interest or pleasure, along with changes in appetite, sleep, sexual drive, and cognition. Often there is a loss of energy, feelings of guilt or low self-worth, and occasional irritability or anxiety like symptoms. These changes are multifactorial in origin and are associated at large with physiological imbalances and a decreased level of certain neurotransmitters in the brain, such as Serotonin and Norepinephrine. Major Depression as a diagnosis is given when these symptoms persist in severity for more than 2 weeks, however there are also other common depressive states such as dysthymia, burnout and often adjustment disorders or even severe stress.

St John’s Wort

St John’s wort (Hypericum Perforatum) is widely used for treating patients with depressive symptoms. A large meta-analysis published in the Cochrane review found that St John’s wort was superior to placebo; as effective as standard anti-depressants; and had fewer side effects than anti-depressants6. St John’s wort may potentiate other similar acting drugs and long-term therapy has been shown to induce enzyme CYP3A (part of the human cytochrome P450 system)7- thus altering metabolism of certain drugs. We therefore recognize that such therapeutic agents should only be prescribed under supervision of a qualified health practitioner.

The above-mentioned meta-analysis selected only double blind randomized trials that compared St John’s wort to placebo or standard antidepressants. Each trial also assed clinical outcomes of depressive symptoms in patients diagnosed with major depression. 12 studies were chosen with a total of 5489 patients. The 18 trials with comparisons to placebo showed marked heterogeneity, whilst the 17 comparisons to synthetic standard antidepressants were statistically homogenous. The results of the trials were as follows:

“In nine larger trials the combined response rate ratio (RR) for Hypericum extracts compared with placebo was 1.28 (95% confidence interval (CI), 1.10 to 1.49) and from nine smaller trials was 1.87 (95% CI, 1.22 to 2.87)”6

“Compared with tri- or tetracyclic antidepressants and selective serotonin reuptake inhibitors (SSRIs), respectively, RRs were 1.02 (95% CI, 0.90 to 1.15; 5 trials) and 1.00 (95% CI, 0.90 to 1.11; 12 trials)”6

“Patients given Hypericum extracts dropped out of trials due to adverse effects less frequently than those given older antidepressants (odds ratio (OR) 0.24; 95% CI, 0.13 to 0.46) or SSRIs (OR 0.53, 95% CI, 0.34-0.83)”6

Tryptophan & 5HTP

Tryptophan is an essential amino acid that is converted in the body to 5-hydroxytryptophan (5HTP) and then into serotonin (5HT). A depleted state of Serotonin is associated with depressive symptoms. Serotonin is predominately a neurotransmitter that modulates mood, sleep and volition. SSRI’s and Tricyclic’s are the most commonly used anti-depressants in the medical sector and they work predominately by increasing serotonin levels in the brain. Serotonin that is synthesized in the body (95% in the digestive tract) cannot pass through the blood brain barrier (BBB) and therefore does not enter the brain and oral supplementation thereof has no effect. However, Tryptophan and 5HTP (as found in Affect D) are able to enter the central nervous system through the BBB and can be used to synthesise Serotonin in the central nervous system.

A Cochrane Review in 2001 of 108 trials involving tryptophan and 5HTP supplementation in unipolar depression revealed that enhanced mood and reduced depression scores in supplemented patients where significantly greater than the Placebo control groups. The selection criteria for inclusion into the systematic review were strict and, only quality randomized control trials with minimal bias were used for analysis. Although only two trials were selected with a total of 64 patients, the results were significant: Tryptophan and 5HTP “were better than placebo at alleviating depression (Peto Odds Ratio 4.10; 95% confidence interval 1.28-13.15; RD 0.36; NNT 2.78) ” The Systematic review further concludes that “Available evidence does suggest that these substances are better than placebo at alleviating depression”, however recommends that further studies, such as large DBRCT, be performed before widespread use as an antidepressant can be recommended. 8

To highlight one such study where 115 patients over a 3 months period with mild to moderate depression were given 5HTP. The results concluded that 5HTP is better than placebo, as good as tricyclic antidepressant (commonly used for Depression – also increasing 5HT &NE- and as good as SSRI’s). Furthermore the 5HTP group had fewer side effects than Tricyclics.9

For depressive states that are being treated by a qualified health practitioner- including psychotherapy and appropriate monitoring- the therapeutic effect of affect D’s 5HTP, Tryptophan and St John’s wort can certainly be a useful adjunct in the therapeutic management plan. The levels of 5HTP and Tryptophan found in Affect D have been carefully calculated according to research that has been conducted and complies with safety regulations. Anecdotally Dr’s using Affect D in their practice has found great results and regularly prescribe to selected patients.

S-adenosyl methionine

S-adenosyl methionine (SAM-e) is a natural occurring compound that readily donates a methyl group- an important step in the path of serotonin production in the brain. A Meta-analysis in 1994 revealed that SAM-e certainly had a greater response in treatment of depression that did any placebo group. In one smaller study, the effect was comparable to standard tricyclic antidepressants.10 some advantages in the above mentioned trials include fewer reported side effects and more rapid onset of action. Further larger studies however are needed to determine the full value of SAM-e and its role in treatment of depression.

A more recent study (2004) involving HIV patients with major depression revealed significant results through supplementation of Vitamin b12, Folic acid and high dose SAM-e. All three compounds are involved in the methylation process and may assist with increasing levels of serotonin in the brain. The study found that symptoms of depression were significantly reduced and the supplements well tolerated. (R Shipley- BMC Psychiatry). One of the confounding elements to this trial was its lack of placebo group, however the previously mentioned trials have indicated SAM-e’s therapeutic value over and above placebo.11

Other Ingredients

In a similar model to tryptophan being a pre-cursor to Serotonin, Phenylalanine is a precursor of norepinephrine, and has been suggested to reduce depressive symptoms in certain patients by promoting the synthesis of Norepinephrine (NE). These studies however were small in number and without placebo control- they are insufficient for statistical analysis, however future trials hold promise.

Curcuma longa is a traditional Chinese medicine, which has been used to effectively manage stress and depression-related disorders in China. Traditional experience and long –term historical use suggest safety efficacy. Curcumin (extract from Curcuma longa) has been shown in animal models (rats) to modify depressive-like behaviour, reduce stress response and restore low levels of serotonin in the brain. This study provides a potential monoaminergic neurotransmitter theory of anti-depressant effect. 12,13

Bupleurum falcatumis another frequent ingredient of anti-depressant formulas used in Chinese medicine. Studies have suggested an influence on depressive behaviour in mice in a dose dependent manner.14

Magnolia Officinalis is another therapy considered as an adaptogen in Chinese medicine with mood modulating properties. Similar animal studies as mentioned above have suggested an influence depressive like behaviour in mice.15

Vitamin B6, Vitamin V12 and Folate assist in methylation and may assist in lowering homocysteine levels associated with depression. Observational studies strongly suggest that supplementation with these vitamin help reduce depressive symptoms, however a current randomized trial is hoping to substantiate the therapeutic effect of lowering homocysteine levels in the treatment of depression in later life.16

One trial looked at Vit B6, Vit B12 and folic acid supplementation in preventing post stroke depression. The results of this randomized double blind placebo-controlled trial was significant: a reduction in the hazard of major depression in the post stroke patient population.17 Results were as follows:

“Among 273 people who completed the final assessment after 7.1 ± 2.1 years (mean ± standard deviation) of follow up, random assignment to B-vitamins was associated with a lower hazard of major depression compared with placebo (18.4% vs 23.3%, adjusted hazard ratio [HR] = 0.48; 95% confidence interval [CI] = 0.31-0.76) and a trend toward a lower odds of major or minor depression at the end of the trial compared with placebo (19.1% vs 27.7%; adjusted odds ratio [OR] = 0.58; 95%CI = 0.31-1.09).”17

Zinc supplementation has been shown to reduce depressive symptoms in mice, and later a randomized placebo control trial revealed statistically significant results in patients with major depression who received Zinc supplementation for 12 weeks. Using the Becks depression scale, depressive symptoms were significantly reduced after 6 weeks of treatment with zinc supplementation, and results over and above placebo became apparent from as early as 2 weeks.18

dl-Tetrahydropalmatine (dl-THP), a naturally occurring alkaloid, has been intensively studied for its sedative and hypnotic effects. Putative explanation for its mechanism and target of action involves the dopaminergic neurotransmission system.19 It acts as an anxiolytic-hypnotic.20

Affect D therefore combines proven natural anti-depressant with selective B vitamins and Zinc, and traditionally used innocuous herbal remedies that suggest benefit in depressive states through animal model and observational studies; to create a therapeutic formula that qualified health practitioners may use increase their therapeutic choice in treatment of depression and depressive states.

References

Ernst E, Rand JI, Stevinson C. Complementary Therapies for Depression; An Overview. Arch Gen Psychiatry. 1998;55:1026-1032.

Stankovic V, Vasiljevic N, Culafic A, Gligorijevic J. Depression and nutrition. Conference       EkoIst 06: 14. Naucno-strucni skup o prirodnim vrednostima i zastiti zivotne sredine [i] 19. Dani preventivne medicine Timocke Krajine, Sokobanja (Serbia), 4-7 Jun 2006. Pp. 229-33

Aneshensel CS, Frerichs RR & Huba GJ. Depression and Physical Illness: A Multiwave, Nonrecursive Causal Model. Journ Health Social Behavior. 1984 Vol. 25 Pp. 350-71

Kessler RC, Soukup J, Davis RB, Foster DF, et al. The Use of Complementary and Alternative Therapies to Treat Anxiety and Depression in the United States. Am J Psychiatry 158:289-294, February 2001

Pennington K, Föcking M, McManus CA, Pariante CM, et al. J Psychopharmacol July 2009 vol. 23 no. 5 Pp. 520-30. DOI:10.1177/0269881108091075

Linde K, Berner MM, Kriston L. St John's wort for major depression. Cochrane Database of Systematic Reviews 2008, Issue 4. Art. No.: CD000448. DOI: 10.1002/14651858.CD000448.

Wang Z, Gorski JC, Hamman MA, Huang SM, Lesko LJ, Hall SD. The effects of St John's wort (Hypericum perforatum) on human cytochrome P450 activity. Clinical Pharmacology and Therapeutics. 2001 Oct;70(4):317-26.

Shaw KA, Turner J, Del Mar C. Tryptophan and 5-Hydroxytryptophan for depression. Cochrane Database of Systematic Reviews 2002, Issue 1. Art. No.: CD003198. DOI: 10.1002/14651858.CD003198

Thomson J, Rankin H, Ashcroft GW, et al. The treatment of depression in general practice: a comparison of L-tryptophan, amitriptyline, and a combination of L-tryptophan and amitriptyline with placebo. Psychological Medicine, 1982;12:741-751.

Bressa GM, S-adenosylmethionine (SAM-e) as an antidepressant: meta-analysis of clinical studies. Acta Neurol Scand Suppl,1994, 154:7-14.

R Shippy, D Mendez, K Jones, I Cergnul, S E Karpiak, S-adenosylmethionine (SAM-e) for the treatment of depression in people living with HIV/AIDS, BioMed Central, Psychiatry, November 2004, 4:38. (http://www.biomedcentral.com/1471-244X/4/38)

Ying Xu, Bao-Shan Ku, Antidepressant effects of curcumin in the forced swim test and olfactory bulbectomy models of depression in rats. Department of Pharmacoology, Peking University, China, August 2005.

Xia, G. Cheng, Y. Pan, Z.H. Xiaa, L.D. Kong, Behavioral, neurochemical and neuroendocrine effects of the ethanolic extract from Curcuma longa L. in the mouse forced swimming test. Journal of Ethnopharmacology Volume 110, Issue 2, 21 March 2007, Pages 356-363

Kwon S, Lee B, Kim M, Lee H, Park HJ, Hahm DH, Antidepressant-like effect of the methanolic extract from Bupleurum falcatum in the tail suspension test. Acupuncture and Meridian Science Research Center, Kyung Hee University, Seoul, 130-701, Republic of Korea, 2009.

Yi LT, Xu Q, Li YC, Yang L, Kong LD. Antidepressant-like synergism of extracts from magnolia bark and ginger rhizome alone and in combination in mice. Progress in Neuropsychopharmacology and Biological Psychiatry. 2009 Jun 15;33(4):616-24. Epub 2009 Mar 11.

AH Ford, L Flicker, K McCaul, F van Bockxmeer, S Hegarty, V Hirani, S Fenner, OP Almeida. The B-VITAGE trial: A randomized trial of homocysteine lowering treatment of depression in later life. Clinical trials registry ACTRN12609000256279. Protocol phase.

Almeida OP, Marsh K, Alfonso H, Flicker L, Davis TM, Hankey GJ. B-vitamins reduce the long-term risk of depression after stroke: The VITATOPS-DEP trial. Annuals of Neurology., 2010 Oct;68(4):503-10.

Nowak G, Siwek M, Dudek D, Zieba A, Pilc A. Effect of zinc supplementation on antidepressant therapy in unipolar depression: a preliminary placebo-controlled study. Polish Journal of Pharmacology. 2003 Nov-Dec; 55(6):1143-7.

Leung WC, Zheng H, Huen M, Law SL, Xue H. Anxiolytic-like action of orallyadministered dl-tetrahydropalmatine in elevated plus-maze. ProgNeuropsychopharmacol Biol Psychiatry. 2003 Aug;27(5):775-9.

Xu Z, Wang F, Tsang SY, Ho KH, Zheng H, Yuen CT, Chow CY, Xue H.Anxiolytic-Like Effect of baicalin and its additivity with other anxiolytics. Planta Med. 2006 Feb;72(2):189-92.

Treatment of depression: time to consider folic acid and vitamin B12

Coppen A & Bolander-Gouaille C. J Psychopharmacol January 2005 vol. 19 no. 1 59-65. doi: 10.1177/0269881105048899

We review the findings in major depression of a low plasma and particularly red cell folate, but also of low vitamin B12 status. Both low folate and low vitamin B12 status have been found in studies of depressive patients, and an association between depression and low levels of the two vitamins is found in studies of the general population. Low plasma or serum folate has also been found in patients with recurrent mood disorders treated by lithium. A link between depression and low folate has similalrly been found in patients with alcoholism. It is interesting to note that Hong Kong and Taiwan populations with traditional Chinese diets (rich in folate), including patients with major depression, have high serum folate concentrations. However, these countries have very low life time rates of major depression. Low folate levels are furthermore linked to a poor response to antidepressants, and treatment with folic acid is shown to improve response to antidepressants. A recent study also suggests that high vitamin B12 status may be associated with better treatment outcome. Folate and vitamin B12 are major determinants of one-carbon metabolism, in which S-adenosylmethionine (SAM) is formed. SAM donates methyl groups that are crucial for neurological function. Increased plasma homocysteine is a functional marker of both folate and vitamin B12 deficiency. Increased homocysteine levels are found in depressive patients. In a large population study from Norway increased plasma homocysteine was associated with increased risk of depression but not anxiety. There is now substantial evidence of a common decrease in serum/red blood cell folate, serum vitamin B12 and an increase in plasma homocysteine in depression. Furthermore, the MTHFR C677T polymorphism that impairs the homocysteine metabolism is shown to be overrepresented among depressive patients, which strengthens the association. On the basis of current data, we suggest that oral doses of both folic acid (800 µg daily) and vitamin B12 (1 mg daily) should be tried to improve treatment outcome in depression.