An Integrative Approach to the Prevention and Treatment of Postpartum Depression (PPD) and Postpartum Anxiety Disorder (PPA)

Dean Raffelock, D.C., L. Ac, CCN, DACBN, DIBAK

Hyla Cass, M.D.

Postpartum depression (PPD) Postpartum Anxiety (PPA) have become a national epidemic in the United States, affecting 15%-20% of all new mothers, or about 600,000-800,000 women annually. (1) It is now estimated that over 30 million Americans are on antidepressant or anti-anxiety medications. (2) The majority of this 30 million are women who have one or more children. The chance of suffering from PPD increases with each successive child. (3)

The most common medical treatment for postpartum depression is SSRI (selective serotonin reuptake inhibitors) antidepressant drugs. Postpartum Anxiety Disorder is most commonly treated by the benzodiazepine family of drugs like Valium, Ativan, Xanax, and Klonopin. Combination reuptake inhibitors for both serotonin and norepinephrine (SNRIs) are also commonly used in postpartum depression. In the case of postpartum psychosis, antipsychotic drugs are used and are immediately necessary. Many women are now given samples of SSRIs as they are leaving the maternity ward. Most medical sources believe that PPD is caused by an imbalance of brain chemistry and that pharmaceutical intervention is the treatment of choice. While a certain percentage of women suffering from PPD do need pharmaceutical assistance, these are far fewer than are actually receiving them. Recent Meta-studies show this to be true.  While it is clear that some women with PPD do need and benefit from pharmaceutical intervention, it is our experience that an integrative approach yields the best results.

 

Postpartum Anxiety Disorder is mostly treated

The most common Postpartum Depression symptoms  include the following:

1. Persistent feelings of despair and/or anxiety;
2. Loss of energy and low levels of daily functioning;
3. Sleep and eating disturbances;
4. Inability to focus, concentrate or make decisions;
5. Feelings of worthlessness, shame and guilt;
6. Feelings of indifference and/or resentment towards the baby;
7. Intrusive negative thoughts and/or obsessive worries–in the most serious cases, this includes thoughts of harming oneself or the baby;
8. Reduced sex drive;
9. Loss of joy and appreciation for life;
10. Irritability or excessive anger.

The literature generally outlines several types of postpartum disorders that have special features beyond the typical symptoms of depression. These include:

1. Postpartum Anxiety Disorder (PPA). Here, the primary symptoms are excessive nervousness, hyper-vigilance, racing thoughts and in some cases outright panic. Panic attacks are especially frightening–sufferers often believe they are dying, as they experience shortness of breath, dizziness and a pounding chest.

2. Postpartum Obsessive-Compulsive Disorder. Most often, this takes the form of obsessive thoughts or worries about the baby and may be accompanied by compulsive behaviors such as constantly checking if the baby is breathing, constantly washing to protect the baby from germs, etc. The most disturbing type of obsessive thoughts are those in which the mother envisions harming her baby in some way. These thoughts are unwanted, intrusive and terrifying to the mother. It is important to emphasize that, except in extremely rare instance of psychosis (see below), these thoughts are not accompanied by any actions. Nonetheless, the mother may be so frightened by her own thoughts that she avoids the baby and consequently neglects her. It is terribly difficult for new mothers to acknowledge having such thoughts, and as a result, many suffer in isolation.

3. Post-traumatic Stress Disorder. PTSD can occur in response to a real or perceived traumatic childbirth or because of unresolved past trauma–sometimes sexual in nature–triggered during childbirth. A woman who experiences PTSD is likely to have recurring, memories, dreams or even flashbacks of the traumatic labor/birth. She will be hyper-vigilant and startle easily, and will likely suffer from sleeplessness, irritability, poor concentration and apathy. Women who have experienced a particularly traumatic childbirth often show symptoms of both PTSD and PPD.

4. Postpartum Psychosis. This is the most extreme and rarest of all postpartum disorders. When it occurs, the mother loses touch with reality and her symptoms may include extreme disorientation (e.g., not knowing who she is), delusional or paranoid thinking, and visual or auditory hallucinations. The few, tragic cases where mothers have harmed their children while in a psychotic state have received enormous media attention. As a result, many people inaccurately associate PPD with psychotic symptoms and dangerous behavior. This constitutes yet another reason why women fail to get help–they want to avoid being labeled with such a stigmatized disorder.

Article Premise: Fully Replenishing a New Mother’s Postpartum Nutritional Reserves Has Been Largely Ignored and Should  be An Integral Part of Treating Postpartum Depression.

Foundations of A Nutritional Approach to PPD
The human body is entirely formed from nutrients. Every muscle, organ, gland, bone, cell, and fluid is composed entirely of nutrients (environmental toxins notwithstanding). All of the neurotransmitters, hormones, biochemical structures, and metabolic pathways are formed from nutrients.

No other normal physiological process uses up and drains more vital nutrients from a postnatal woman’s body than the process of being pregnant, giving birth, and caring for a new infant which may include breastfeeding. The fact that a mother’s body donates all the nutrients required to form her baby’s body is too often overlooked when it comes to the medical treatment of PPD. Not only does the placenta literally rob the mother’s body of all the key nutrients required to make a baby’s body, but the placenta itself is formed from nutrients taken from the mother’s body. This is the main reason that many postpartum women become nutritional drained and this nutrient depletion syndrome can lead to postpartum depression and anxiety disorder.

Other factors that may contribute to a drain of a new mother’s nutrient reserves are loss of blood during the birth process, sleep deprivation, breastfeeding, returning to work too soon, and the immense extra energy required to take care of a new infant with intense needs. If a pregnant woman’s or new mother’s nutrient reserves are too low, she is much more vulnerable to experiencing PPD and PPA because all of the body’s normal metabolic processes are entirely dependent upon nutrients. The preponderance of extremely poor quality pharmaceutical prenatal vitamins significantly adds to the tendency of nutrient depletion.

Rarely is there is any mention that the body’s production of neurotransmitters is completely dependent upon their nutritional precursors. (4) Nor are the causes of these nutritional precursor deficiencies discussed. Additionally, the interdependent relationship between hormones and neurotransmitters is rarely taken into consideration by most physicians when considering treatment for PPD and PPA. The nutritional requirements of mitochondrial function, the importance of liver function from Western and Eastern perspectives, and some individual nutrients like Omega 3 fish oils, pharmaGABA, L-theanine, SAMe, inositol, magnesium, and the herb St. John’s Wort can also be of great assistance in treating PPD and PPA. These will be briefly discussed.

An integrative approach to treating PPD may include nutritional therapies, bio-identical hormone replacement, moderate exercise, a nutrient dense diet, proper rest, psychological counseling/support, stress reduction techniques, elimination of caffeine, alcohol and other addictive drugs, and if needed, pharmaceutical intervention.

Neurotransmitter Nutritional Precursors

Serotonin and Tryptophan

The amino acid L-Tryptophan is required for the body to produce serotonin. Ninety-five percent of the serotonin in the human body is produced in the intestinal tract. Approximately five percent is produced in the brain. The serotonin produced in the intestinal tract is unavailable to the brain because serotonin cannot pass through the blood- brain barrier. L-Tryptophan also does not easily pass through the blood-brain barrier and requires a carrier protein to ferry it into the brain. The consumption of simple sugars changes brain neuron cell membrane amino acid selectivity, allowing tryptophan to enter the brain more easily. Hence, the craving of sweets is often a sign of serotonin deficiency.

Serotonin has been referred to as the brain’s mood elevating and tranquilizing chemical. Inadequate serotonin levels are linked with depression, anxiety, insomnia, irritability, and weight gain. Serotonin mediated depression usually contains an element of anxiety. Serotonin is considered an inhibitory neurotransmitter. Its functions include:

- Inhibiting Glutamate excitability over diverse regions of the CNS
-Stimulating its own receptors on GABA neurons prompting GABA to perform its inhibitory function
- Inhibiting the release of the Catecholamines: Dopamine, Norepinephrine, and Epinephrine.

A comparison of the effects of optimal serotonin levels to low serotonin levels to reveals the following contrasts:

1) Hopeful/optimistic—————-Depressed
2) Calm—————————Anxious
3) Good-natured——————–Irritable
4) Patient————————–Impatient
5) Reflective/ thoughtful————–Impulsive/Reactive
6) Loving /Caring——————–Abusive
7) Able to concentrate—————-Short attention span
Creative/focused——————Blocked/scattered
9) Moderate carbohydrate intake——–Excessive carbohydrate intake
10) Good sleep and dream recall——–Insomnia and poor dream recall

Tryptophan is converted to its metabolite, 5- Hydroxy-Tryptophan (5-HTP) which is then converted to serotonin. Niacin, iron, and folic acid are required for L-Tryptophan to be converted into 5-HTP. The body also requires pyridoxal-5-phosphate along with 5-HTP in order to produce serotonin. Magnesium and riboflavin (B2) are required for the conversion of pyridoxine (B6) into pyridoxal-5-phosphate. Deficiencies in any of these nutrients can limit the production of serotonin. Numerous double-blind studies have shown 5-HTP to be as effective as antidepressant drugs with fewer and milder side effects and most times better tolerated. (5-11)

 

    

From Martin Hintz, M.D. –Neuro Research

 A number of significant factors contribute to low L-Tryptophan levels in many people, especially postpartum women whose bodies are providing the proteins needed to form another human body, these include excessive levels of cortisol, epinephrine, norepinephrine, and dopamine. The ratio of L-tryptophan to other amino acids available in most foods is quite low.

An overabundance of the adrenal gland hormone cortisol (a very common occurrence in stressful psychological and physiologic states) adversely affects serotonin production and sensitivity in four different ways:

1. Excess cortisol significantly decreases the number of serotonin (5-HT1A) receptor sites. (12)
2. Excess cortisol suppresses serotonin receptors. (13, 14)
3. Excess cortisol increases serotonin reuptake. (15)
4. Excess cortisol, causes tryptophan oxygenase (TO) to metabolize tryptophan into kynurenine, leaving less tryptophan to become serotonin. (15,16)

If cortisol levels are too low in the amygdala, serotonin no longer has an Inhibitory effect on Glutamatergic activity, suggesting that cortisol plays a key role in maintaining Serotonergic-mediated modulation. (16,17) This may be another factor involving insomnia in PPD.

Added to the reasons that serotonin deficiencies are growing more common and contributing to PPD is a stress-related overabundance of the catecholamines. Epinephrine, norepinephrine, and dopamine also deplete serotonin because the inhibitory monoamine neurotransmitter serotonin is supposed to balance these three excitatory monoamine neurotransmitters. The more stress a person experiences, the more the body increases the production of the catecholamines in an attempt to respond to this stress. This requires a postpartum body to produce even more serotonin – though deficiencies in nutrient precursors may interfere with its production.

The use of 5-HTP as a nutritional precursor to serotonin has significant advantages over tryptophan. 5-HTP easily passes directly through the blood-brain barrier without the need for a carrier protein, allowing for an easier conversion into serotonin in the brain. Sublingual forms of 5-HTP work more quickly. Dosage varies from 25 mg per day to 300 mg per day or more.

A deficiency of vitamin B6 (pyridoxine), which is required for serotonin synthesis, is often found in premenopausal female patients with depression. (18) Replacing B6 in cases of deficiency is an important aspect of PPD treatment that may enhance serotonin production in the brain. (19) The use of the vitamin B6 metabolite, pyridoxal-5-phosphate, instead of B6 is suggested especially when magnesium and/or riboflavin deficiencies are suspected or confirmed. There is some controversy whether it is best to supplement 5-HTP and pyridoxal-5-phosphate together or take them separately, adhering to a two-hour wait period. Our clinical experience indicates that it fine to supplement them together. Many products including a combination of 5-HTP and P-5-P are available.

Some controversy exists regarding the simultaneous use of SSRIs and serotonin nutritional precursors. The pharmaceutical companies seem adamant about avoiding this and often mention the possibility of Serotonin Syndrome, a dangerous condition generally brought about by combining serotonin enhancing medications, especially MAO inhibitors, with medications, herbs, or nutritional precursors that also enhance serotonin activity. Symptoms of serotonin syndrome may include nausea, headache, agitation, diaphoresis, hypertension, tachycardia, and hyperthermia that can go over 104 F. This appears a remote possibility at best when just using 5-HTP or using 5-HTP in combination with one SSRI medication. (20)

SSRIs appear to not only keep serotonin in the neuron synapses longer by inhibiting reuptake, but also by pulling the nutritional precursors for serotonin from the storage vesicles and reuptake ports. In fact, in our clinical experience, many women with PPD do better when taking 5-HTP and P-5-P along with their SSRIs than taking SSRIs alone. Serotonin precursor deficiencies may be the reason that SSRIs don’t work for some, work and then stop working for others, and why it is not unusual for a woman with PPD to have been prescribed two or more different SSRIs over time. The SSRIs do not give a net increase of serotonin so they need enough available serotonin in order to have enough to re-uptake.

 

Dr. Dean Raffelock- catacholamine chart

The catecholamines are predominantly energizing and mood elevating when produced at appropriate levels. Synthesis of the catecholamines occurs in the CNS, adrenal medulla, and peripheral sympathetic neurons. Norepinephrine and dopamine act primarily as neurotransmitters in the CNS. Epinephrine acts primarily as an adrenal hormone to mobilize energy.

The catecholamines influence most organ systems. When levels are excessive they are catabolic and can lead to the body metabolizing its own nerve, muscle and bone tissue. Low levels can lead to depression, fatigue, and weight gain.

Dopamine: Dopamine is the catecholamine precursor for norepinephrine and is found both in the CNS and adrenal medulla. Its functions include motor function and posture, cognitive function (attention, focus, working memory and problem solving), and pleasure sensations. Dopamine can act either as an inhibitory or excitatory neurotransmitter in response to incoming afferent signals.

Norepinephrine (noradrenaline): CNS norepinephrine mediates mood regulation, drive, ambition, learning and memory, alertness, arousal and focus. Clinically, there is often an inverse relationship between norepinephrine (excitatory) and serotonin (inhibitory). When serotonin is low, norephinephrine may be over-upregulated, resulting in “fight or flight” responses leading to anxiety and/or panic attacks. Over-expression of CNS norepinephrine is clinically associated with anxiety, aggression, irritability, mania or bipolar disease, immune suppression, and hypertension; low norepinephrine is associated with atypical depression, with symptoms of fatigue, hypersomnia, hyperphagia, lethargy and apathy.
(21,22)

Epinephrine (adrenaline): Epinephrine synthesis is dependent upon norepinephrine being converted into epinephrine by methylation.
Hans Selye (1974) described the three phase s of the “General Adaptation Syndrome” to stress (23):

Phase I: Alarm reaction: high epinephrine/high cortisol

Phase II: Resistance: high cortisol/low DHEA, variable epinephrine

Phase III: Exhaustion: depletion of cortisol, epinephrine and DHEA
Adrenal exhaustion is a major factor in depression related to chronic or severe stress.

A woman suffering from PPD should be closely questioned about her symptoms; SSRIs are routinely given to women who have functional hypoadrenia involving the adrenal cortex and/or medulla, or low thyroid function (discussed below). Low glucocorticoid and/or catecholamine levels can cause the symptoms of fatigue, malaise, and depression. (24,25)

Many women with PPD require pharmaceuticals and/or nutriceuticals that address deficiencies in both serotonin and the catecholamines. Nutritional therapies for catecholamine balance include:

§ DL-phenylalanine and L-tyrosine, the amino acid precursors for epinephrine, norepinephrine, and dopamine. DL-phenylalanine also helps to increase endorphins, which are mood-elevating. Many PP women diagnosed with bipolar disorder will respond well to high dose DL-phenylalanine therapy (26), along with serotonin precursors and high-dose (6 grams per day) omega-3 fatty acids in the form of fish oils. (27)

§ L-cysteine, sulfur, iron, and folate, required for conversion of L-tyrosine into L-dopa.

§ Pyridoxal-5-phosphate, required for the conversion of L-dopa into dopamine. Copper and vitamin C are required to convert dopamine into norepinephrine. Pridoxal-5-phosphate, B12, and folic acid are required to convert norepinephrine into epinephrine.

Gamma-Aminobutyric Acid (GABA)

GABA is the most important and widespread inhibitory neurotransmitter in the brain. Low levels of GABA are particularly important to look for when anxiety and insomnia are included in the symptom display of PPD/PPA. GABA is essential for balancing excitatory neurotransmitters and hormones such as cortisol, epinephrine, norepinephrine, and glutamate. Too much excitation without adequate GABA inhibition can lead to: (28)

- Insomnia
- Restlessness
- Irritability
- Anxiety
- Panic Attacks
- Seizures

GABA’s job clinically is to induce relaxation, calmness and aid sleep. Where there are glutamate receptors (powerful excitatory neurons), there will be GABA receptors nearby. GABA allows only the most important excitatory signals to pass by and dampens or quenches extraneous excitatory signals when GABA levels are adequate.

Benzodiazapines (Valium, Klonopin, Zanax, Ativan, etc.) and sleep pharmaceuticals like Ambien and Sonata work on GABA receptors, as does moderate alcohol consumption. L-theanine, lactium (milk peptides), L- glutamine, taurine, and bio-identical progesterone can act as nutraceutical/hormonal GABA agonists. The drug Gabatril is a GABA re-uptake inhibitor as is Valerian extract. A newer nutriceutical product called pharmaGABA seems to yield more effective results than synthetic GABA.

From a Chinese Medicine perspective, serotonin and GABA would be Yin (relaxing, harmonizing, cooling, nurturing, moisturizing, inhibitory) and the catecholamines would be Yang (energizing, mobilizing, warming, excitatory, drying). From both Eastern and Western perspectives, it is important to balance these opposing groups of brain chemicals to obtain balance. A woman with PPD who now has more energy but can’t sleep is just as unhappy as a woman who now can sleep but who is even more lethargic than before treatment.

Balancing neurotransmitters is key. Balancing neurotransmitters and hormones is clinically even more effective.

Hormone-Neurotransmitter Interactions

The relationship between neurotransmitters and hormones in PPD is often overlooked. Neurotransmitters and neuropeptides are required in order to mediate hypothalamic production of releasing hormones, enabling the pituitary gland to properly conduct the hormonal orchestra. The hypothalamus is considered a key part of the mid-brain, the “emotional brain,” so there is little wonder why imbalances in neurotransmitters and hormones can adversely affect emotional states.

Thyroid hormones. The catecholamines and thyroid hormones are closely related in many of their functions. L-tyrosine, along with iodine, is the precursor for thyroglobulin and thyroid hormones T-3 and T-4. A depression with no anxiety, with the predominant symptoms of exhaustion and difficulty stringing multiple positive thoughts together, is most often associated with low adrenal (29) and/or thyroid function (30-32) and generally doesn’t respond well to SSRIs or serotonin nutritional precursor therapy.

It is well known that low thyroid function can cause physiologic depression and fatigue. Giving T3 induces a rise in serotonin, and in animals with hypothyroidism, serotonin synthesis is reduced. (33) T3 appears to desensitize presynaptic Serotonin autoreceptors. (34) Conversely, the diurnal peak of TSH, observed during the physiological circadian rhythm, is serotoninergic dependent. (35)

Thyroid function and serotonin function are interdependent both clinically and bio-chemically. Optimal thyroid function is dependent on optimal serotonin levels. Optimal serotonin balance is dependent on optimal thyroid function. TSH increase is dependent on adequate serotonin stimulation of hypothalamic TRH, allowing TSH to rise. (36) Suppressed TSH currently may more appropriately represent low serotonin states than any real assessment of true thyroid function. The thyroid hormone triiodothyronine (T3) augments and accelerates the effects of antidepressant drugs. Fluoxetine + T3 are better at desensitizing 5-HT hypothalamic autoreceptors than either alone. (37-39)

Estrogen: A growing body of evidence points to estrogen’s importance in serotonergic function. (40) Estrogen inhibits serotonin reuptake. (41,42) Estrogen treatment is shown to selectively enhance serotonin (5-HT1A-mediated) responses in the hippocampus (43,44) Estrogen increased the firing activity of 5-HT (serotonin) neurons in both male and female rats. (45,46) In short, estrogen appears to be nature’s SSRI.

Presently, there is a great deal of controversy regarding estrogen HRT. The HERS study and WHI studies have stirred the controversy without making the important distinction between bio-identical and pharmaceutically altered estrogens; neither is any distinction made between progesterone and progestins. The clinician is encouraged to become very well versed in this area regarding risks versus benefits of HRT. Many women with PPD can benefit from low-dose bio-identical estrogen HRT if indicated and potential benefits outweigh risks.

Progesterone: Bio-identical progesterone has a known anti-depressant/anti-anxiety effect. Throughout pregnancy, the placenta produces copious amounts of progesterone, increasing blood levels to many times pre-pregnancy levels. Post-partum, this supply is suddenly gone, along with its soothing effects on the mother’s nervous system.
Allopregnanolone is synthesized by the reduction of progesterone via the enzymes 5-reductase and 3-hydroxysteroid dehydrogenase (3-HSD). Allopregnanolone is one of the most potent known modulators of GABA receptors. (47,48) Allopregnanolone has behavioral and biochemical characteristics similar to ethanol, barbiturates, and benzodiazepines. (49,50)

Bio-identical progesterone can be very helpful for women with PPD with anxiety and insomnia. Using the  PharmaGABA and bio-identical progesterone simultaneously is often very helpful to relieve anxiety and sleep issues.

DHEA: DHEA increases the firing activity of serotonin neurons. (51) DHEA also increases dopamine and norepinephrine synthesis via mRNA for tyrosine hydroxylase. (52) Because of this, DHEA can be helpful in some forms of PPD. DHEA also inhibits GABA and is therefore a GABA antagonist. (53) Clinically, if the use of DHEA causes insomnia and irritability, most likely the patient is GABA deficient and this should be addressed before continuing to supplement DHEA.

Testosterone: increases serotonergic neuron firing in the raphe area, increasing mood. (54)

Mitochondrial Function

      

 

from Metametrix Lab- Ion Panel Booklet

 

Inefficient mitochondrial function can limit ATP production, lower energy and contribute to or cause physiological depression. More than 90% of all cellular oxygen consumption is used to fuel mitochondrial metabolism. Mitochondria must transfer huge numbers of electrons to produce energy. Mitochondrial dysfunction can affect all organ systems, including neurons and glands.

Dietary fats, carbohydrates , and proteins all need to be converted into acetyl-coenzyme A (acetyl CoA) before entering the Krebs cycle and electron transport chain. The nutritional precursors required for fatty acids, glycerol, and cholesterol to enter the Krebs cycle and generate ATP are riboflavin (B2), L-carnitine, niacin, and biotin. Thiamin (B1), riboflavin (B2), niacin (B3), pantothenic acid (B5), biotin, and alpha-lipoic acid are required for carbohydrates and proteins to enter the Krebs cycle in the mitochondria.

Within the Krebs cycle, cysteine and iron are needed to convert cis-aconitate to isocitrate. Niacin, magnesium, and manganese are required to convert isocitrate into alpha-ketoglutarate. The amino acids glutamine, histidine, arginine, proline and glycine are needed to form alpha-ketoglutarate. Thiamin, riboflavin, niacin, pantothenic acid, and alpha lipoic acid, are needed to convert alpha-ketoglutarate into succinyl-CoA. The amino acids isoleucine, valine, and methionine are needed to form succinyl-CoA. Magnesium is required to convert succinyl-CoA into succinate. Riboflavin is required to convert succinate into fumarate. The amino acids tyrosine and phenylalanine are needed to form fumarate. Niacin is required to convert malate into oxaloacetate.

All these nutrients are required to produce 36 units of ATP per molecule of acetyl CoA in the Krebs cycle. A significant deficiency of any of these key nutrients can cause mitochondrial dysfunction and contribute to fatigue and depression.

Niacin and coenzyme Q10 are required for oxidative phosphorylation (electron transport chain, or ETC). Normally, the ETC produces another 3 units of ATP in the mitochondria in addition to the Krebs cycle’s 36. A significant deficiency in either of these can also reduce ATP production and contribute to a physiologic depression.

Mitochondrial dysfunction is often overlooked in the treatment of PPD. A study done with postpartum women showed that a comprehensive postnatal nutrient program, including many of the Krebs cycle/oxidative phosphorylation nutrients, relieved many postpartum symptoms including mild to moderate PPD.

Liver Detoxification

 

NUTRITION: A FUNCTIONAL APPROACH-Jeffrey Bland, Ph.D

For many centuries, Chinese medicine has correlated liver meridian dysfunction with anger, irritability, and depression. From this perspective, suppressed anger often leads to depression. Concepts such as rising liver heat and stagnant liver Qi are used to depict how faulty liver meridian function could dramatically affect emotional states. When the flow of electrons within a meridian is up or down-regulated, the organ dependant upon that meridian will become dis-eased. Many practitioners of Chinese medicine are taught to consider the liver the “seat of the emotional body” because of this strong correlation of liver dysfunction with negative emotions.

In the Orient the term “hot liver” is used to depict someone who has anger issues. The English use the “liverish” to describe one who is irritable. From a Western medicine point of view, most clinicians are aware how an alcoholic’s liver cirrhosis can first cause irritability and eventually depression.

In the past two decades much more information has come to light regarding phase one and phase two liver detoxification pathways. These pathways greatly contribute to the body’s ability to excrete exogenous and endogenous toxic chemicals. Environmental toxin levels (xenobiotics) are ever on the rise and require that the liver play a very important role in their excretion.

Added to this burden of detoxification are the internal production of increased stress hormones and other body chemicals that require excretion. All of these chemicals require that the liver have adequate nutrients to facilitate their excretion.

Phase one liver detoxification consists of oxidation, reduction, or hydrolysis. The cytochrome P450 system mixed function oxidases perform the most important beginning function of detoxifying these exogenous and endogenous toxins. Phase I liver detoxification requires an adequate supply of nutrients, enzymes, and antioxidants. This list includes riboflavin, niacin, pyridoxine, folic acid, cobalamin, glutathione, phospholipids, carotenes, vitamin C, bioflavonoids, flavonoids, vitamin E, selenium, copper, zinc, manganese, CoQ10, and nutrients contained in thiols, pycnogenol, and silymarin.

Phase II liver detoxification consists of conjugation pathways in the hepatocytes. Amino acid conjugation (binding) of toxins requires glycine, taurine, glutamine, ornithine, and arginine. Sulfation requires sulfur-bearing amino acids or elemental sulfur. Sulfation is required to break down and package estrogens, DHEA, thyroxine, cortisol, catecholamines, melatonin, ethyl alcohol, bile acids, tyramine, cholecystekinin, cerebrosides and others. Glucuronidation requires magnesium and B6 to break down estrogens, other steroids, melatonin, and many xenobiotics.

Methylation requires B12, B6, and folic acid to break down and eliminate catecholamines, histamine, and many drugs and xenobiotics. Glutathione conjugation helps to detoxify heavy metals and numerous xenobiotics. Glutathione requires glutamate, glycine, and cysteine or N-acetyl-cysteine plus selenium and vitamin C for its formation. Acetylation, another detoxification pathway, requires B2, B5, molybdenum, and vitamin C in order to do its function.Sulfoxidation transforms toxic sulfite molecules into usable sulfates.

Mothers in the U.S have a high toxic burden that is evidenced by the levels of toxins in mother’s milk. (55) If the liver is too burdened and unable to perform its many tasks of detoxification, this may contribute to PPD.

Omega-3 Fatty Acid Deficiencies and PPD

A deficiency of omega-3 fatty acids has been linked with depression. (56-59) Numerous studies have demonstrated the efficacy of fish oil supplementation in depression. (60,61)

The human brain is 60% fat. The quality of fats that compose neurons significantly influence brain function including moods. A relative deficiency of flexible omega-3 fatty acids compared to the more rigid omega-6, saturated, and cis-trans fatty acids impairs the function of cell membranes and their ability to selectively allow passage of molecules in and out of neurons. The brain is composed of and uses more fatty acids than any other body structure. DHA – referred to by Allport as the “queen of fats” (62) – is responsible for the fastest cellular movements. As the primary structural and cognitive fat of the brain, DHA also affects moods.

A developing fetus’ brain, nerves, eyes, skin, and cellular membranes all require omega-3 oils, especially DHA. The placenta selectively removes omega-3 oils from the mother’s blood stream via the placenta often leaving the mother significantly deficient in these essential oils. (63,64). The recommended dose for omega-3 fish oils when treating PPD is 6-12 grams per day.

Hypericum perforatum (St. John’s Wort):

Over twenty-five double-blind studies have shown the herb St. John’s Wort to produce as good or better results compared to SSRI drugs with significantly fewer side effects. (65-71) In Germany, where hypericum is a prescription drug and covered by insurance, over 20,000,000 take this herb for depression. One of the benefits of taking St. John’s Wort is an increase of serotonin. (72)

SAMe (S-adenosylmethione):

SAMe is a methyl donor in the production of monamines, neurotransmitters, and phospholipids such as phosphatidylserine and phosphatidylcholine. SAMe serves as a precursor for glutathione, coenzyme A, cysteine, taurine, and other essential compounds. SAMe is involved in converting methionine into sulfur and is important in homocysteine metabolism.

When compared with other antidepressants, SAMe tend to work faster and more effectively with virtually no negative side effects. In fact, SAMe has beneficial side effects including improved cognition, slowing of the aging process, improved joint function and less pain, and liver protection. (73)

Normally the brain synthesizes adequate SAMe from the amino acid methionine. Supplementing SAMe in depressed patients increases serotonin and dopamine levels, improves membrane fluidity, and improves the binding of neurotransmitters to receptor sites (74,75). Numerous double-blind studies demonstrate the efficacy of SAMe for depression. (76-78) The suggested dose of SAMe to treat depression ranges from 400-1600 mg a day.

Inositol

Depressed patients have lower brain levels of inositol. (79) Inositol is useful in maintaining healthy serotonin metabolism, and by doing so helps treat many conditions like depression, agoraphobia, panic disorder (80-82), and obsessive compulsive disorder (83).
Research shows that taking 6-12 grams of inositol per day for 4 weeks significantly improves mood and reduces the severity of depression. (84-86) Inositol can be safely used with antidepressant medications. (87)

L-Theanine

L-theanine is known to increase levels of GABA and has an anti-anxiety effect as well as improving cognitive function. (88) L-theanine may also normalize dopamine levels which are often depleted by various stresses. (89) L-theanine significantly reverses glutamate-induced toxicity. (90)

 

Integrating High Quality, High Potency Prenatal and Postnatal Nutrient Systems into Preventing and Treating Postpartum Depression and Anxiety 

 

Clinically it is imperative that higher quality, higher potency, more comprehensive prenatal an postnatal nutrient systems be utilized in the treatment and prevention of postpartum depression. It is common knowledge in many 3rd world countries that the postpartum recovery period is 24 months because this is the amount of time women are told to wait between pregnancies to replenish their bodies and avoid many postnatal health problems. These women have more community and extended family support too which significantly reduces the incidence of PPD.

Most prenatal vitamin supplements are inadequate to fully supply developing baby and mother with the potency and quality of nutrients required to fuel pregnancy and the postpartum periods. These are highly nutrient dependent process.
A randomized, double-blind, placebo-controlled clinical trial done on a comprehensive postnatal nutrient program called After Baby Boost showed excellent results, improving 14 common postpartum symptoms including postpartum depression, anxiety, insomnia and mood swings. Parameters measured were breast tenderness, concentration, cramping, depression, dizziness, fatigue, headaches, insomnia, irritability, joint inflammation and pain, mood swings, nervousness, palpitations, sweating, temperature changes (hot or cold), vaginal dryness, and water retention.

After Baby Boost contains high-potency vitamins and minerals including CoQ10, alpha lipoic acid, 2 grams of fish oils with 3 antioxidants to prevent rancidity, and nighttime minerals (calcium and magnesium citrate). The placebo used was a leading prenatal vitamin.

After Baby Boost significantly outperformed the prenatal vitamin in all 14 symptom categories, indicating that most postpartum women require more comprehensive, higher potency nutrient replenishment than prenatal vitamins provide. (91)

Obstetricians rarely stress the importance of a high-quality, nutrient dense diet. Nor do they prescribe high quality prenatal vitamins.  Women are often told, “you are eating for two now, so eat whatever you want.” In actuality, only 300 extra calories are needed per day during pregnancy. It is important that these be nutrient-dense calories. Unrestricted eating of carbohydrates contributes to obesity and can contribute to metabolic diseases including physiologic depression and even, diabetes of pregnancy.

Integrative PPD Treatment

It is hoped that the reader becomes more aware of this simple concept: A baby’s body is entirely composed of the nutrients donated by its mother’s body. Because all physiologic processes and chemicals (neurotransmitters, hormones, metabolic pathways, etc.) are nutrient dependent, nutritional deficiencies can often be the fundamental cause of PPD. While antidepressant drugs are necessary for some, the longer-term solution often requires a well-thought-out integrative approach that includes (1) replenishing nutritional reserves through dietary supplements,(2) psychotherapy and/or  childbirth/PTSD therapies such as EMDR, (3)adequate sleep (often very difficult with a new infant), (4) moderate exercise, (5) deep belly breathing/meditation, (6) community support, (6) a nutrient dense diet, and (7) drug therapy when necessary

REFERENCES

1. Gaynes BN, Gavin N, Meltzer-Brady S, et al. “Perinatal depression: prevalence, screening accuracy, and screening outcomes,” Agency for Healthcare Research and Quality, U.S. Department of Health and Human Services, Rockville, MD: AHRQ Publication #05-E006-2, February 2005.

2. No authors listed. “Medication Therapy in Ambulatory Care: United States, 2003-2004,” Centers for Disease Control Vital and Health Statistics, posted at http://www.cdc.gov/nchs/data/series/sr_13/sr13_163.pdf.

3. Willen JM, Mounts KO. “Women with depression: ‘You can’t tell by looking,’” Matern Child Health J 2006 September; 10(Suppl 7): 183-187.

4. Wurtman RJ, Fernstrom JD. “Control of brain neurotransmitter synthesis by precursor availability and nutritional state,” Biochem Pharmacol 1976 Aug 1;25(15):1691-6.

5. Birdsall TC. “5-Hydroxytryptophan: a clinically-effective serotonin precursor,” Alternative Medicine Review 1998 Aug; 3(4):271-80.

6. Byerley WF et al. 5-Hydroxytryptophan: A review of its antidepressant efficacy and adverse effects. J Clin Psychopharmacol 1987;7:127-137.

7. Byerley W, Judd L, Reimherr F, Grosser B. 5-hydroxytryptophan: a review of its antidepressant efficacy and adverse effects. J Clin Psychopharmacol. 1987;7:127-137.

8. D’Elia G, Hanson L, Raotma H. “L-tryptophan and 5-hydroxytryptophan in the treatment of depression: a review,” Acta Psychiatra Scand 1978;239-52.

9. Poldinger W, Calanchini B, Schwarz W. “A functional-dimensional approach to depression: serotonin deficiency as a target syndrome in a comparison of 5-hydroxytryptophan and fluvoxamine,” Psychopathology 1991;24:53-81.

10. Shaw K, Turner J, Del Mar C. “Tryptophan and 5-Hydroxytryptophan for depression (Cochrane Review),” The Cochrane Database of Systematic Reviews 2002, Issue 1. Art. No.: CD003198. DOI:10.1002/14651858.CD003198

11. Turner EH, Loftus JM, Blackwell AD. “Serotonin a la carte: supplementation with the serotonin precursor 5-hydroxytryptophan,” Pharmacol Therapeutics 2006;109(3):325-338.

12. Crayton JW, et al. “Effect of corticosterone on serotonin and catecholamine receptors and uptake sites in rat frontal cortex,” Brain Res 1996 Jul 29;728(2):260-2.

13. Tafet GE, Toister-Achituv M, Shinitzky M. “Enhancement of serotonin uptake by cortisol: A possible link between stress and depression,” Cogn Affect Behav Neurosci 2001 Mar;1(1):96-104.

14. Thakore JH, Dinan TG. “Cortisol synthesis inhibition: A new treatment strategy for the clinical and endocrine manifestations of depression,” Biological Psychiatry 1995 Mar; 37(6): 364-368.

15. Altar C, et al. “Glucocorticoid induction of tryptophan oxygenase,” Biochem Pharmacol 1983;32:979-84.

16. Stutzmann GE, McEwen BS, LeDoux JE. “Serotonin Modulation of Sensory Inputs to the Lateral Amygdala: Dependency on Corticosterone,” J Neurosci 1998 Nov 15;18(22):9529-38.

17. Drevetz WC. “Neuroimaging Abnormalities in the Amygdala in Mood Disorders,” Annals of the New York Academy of Sciences 2003;985:420-444.

18. Williams AL, et al. “The role for vitamin B-6 as treatment for depression: a systematic review,” Family Practice 2005 22(5):532-537.

19. Hartvig K, et al. “Pyridoxine effect on synthesis rate of serotonin in the monkey brain measured with positron emission tomography,” Journal of Neural Transmission June 1995;102(2).

20. No authors listed. “Monograph: 5-Hydroxytryptophan,” Alternative Medicine Review 1998;3(3):224-6.

21. Gold PW, Chrousos GP. “Organization of the stress system and its dysregulation in melancholic and atypical depression: high vs low CRH/NE state,” Molecular Psychiatry 2002, Volume 7, Number 3, Pages 254-275.

22. Asnis GM, McGinn LK, Sanderson WC. “Atypical depression: clinical aspects and noradrenergic function,” Am J Psychiatry 1995; 152:31-36.

23. Selye H. Stress Without Distress. Philadelphia: J. B. Lippincott Co., c1974.

24. Sulman FG, Pfeifer Y, Superstine E. “The adrenal exhaustion syndrome: an adrenal deficiency,” Annals of the New York Academy of Sciences 1977;301(1): 918-930.

24. Tsigos C, Chrousos GP. “Hypothalamic-pituitary-adrenal axis, neuroendocrine factors and stress,” J Psychosom Res 2002;53:865-71.

25. Tsigos C, Chrousos GP. “Physiology of the hypothalamic-pituitary-adrenal axis in health and dysregulation in psychiatric and autoimmune disorders,” Endocrinol Metab Clin North Am 1994;23:451-66.

26. Holford P. “Depression: the nutrition connection,” Primary Care Mental Health 2003;1:9-16.

27. Stoll AL, et al. “Omega-3 fatty acids and bipolar disorder: a review,” Prostaglandins Leukot Essent Fatty Acids 1999 May-Jun;60(5-6):329-37.

28. Bowery NG, et al. “International Union of Pharmacology. XXXIII. Mammalian gamma-aminobutyric acidB receptors: structure and function,” Pharmacological Reviews 2002 June;54(2): 247-264.

29. Carroll BJ, Curtis GC, Mendels J. “Cerebrospinal fluid and plasma free cortisol concentrations in depression,” Psychol Med 1976;6:235-44.

30. Joffe R, Roy-Byrne P, Udhe T. “Thyroid function and affective illness: a reappraisal,” Biol Psychiatry 1984;19:1685-91.

31. Gold M, Pottash A, Extein I. “Hypothyroidism and depression: evidence from complete thyroid function evaluation,” JAMA 1981;245:1919-22.

32. Banki C, Arato M, Papp Z. “Thyroid stimulation test in healthy subjects and psychiatric patients,” Acta Psychiatr Scand 1984;295-303.

33. Sintzel F, et al. “Potentializing of tricyclics and serotoninergics by thyroid hormones in resistant depressive disorders,” Encephale 2004 May-Jun;30(3):267-75.

34. Bauer M, et al. “Thyroid hormones, serotonin and mood: of synergy and significance in the adult brain,” Mol Psychiatry 2002;7(2):140-56.

35. Jordan D, et al, “Participation of serotonin in thyrotropin release. II. Evidence for the action of serotonin on the phasic release of thyrotropin,” Endocrinology 1979;105: 975-979.

36. Karamouzis M, et al. “The response of thyroid hormones FT3, FT4, TSH, serotonin and histamine in young persons during maximal physical work,” Hell J Nucl Med 1999;2:125-30.

37. Abraham G, Milev R, Lawson JS. “T3 augmentation of SSRI resistant depression,” Journal of Affective Disorders 91(2-3):211-215.

38. Aronson R, Offman HJ, Joffe RT, Naylor D. “Triiodothyronine augmentation in the treatment of refractory depression: a meta-analysis,” Arch Gen Psychiatry 1996; 53: 842-848.

39. Lifschytz T, et al. “Basic Mechanisms of Augmentation of Antidepressant Effects with Thyroid Hormone,” Current Drug Targets 2006 Feb;7(2): 203-210.

40. Joffe H, Cohen LS. “Estrogen, serotonin, and mood disturbance: where is the therapeutic bridge?” Biological Psychiatry 1998;44(9): 798-811.

41. Archer JS, “Relationship between estrogen, serotonin, and depression,” Menopause 1999;6(1): 71-78.

42. Koldzic-Zivanovic N, et al. “Intracellular signaling involved in estrogen regulation of serotonin reuptake,” Mol Cell Endocrinol 2004 Oct 29;26(1-2):33-42.

43. Bethea CL. “Ovarian Steroid Regulation of 5-HT1A Receptor Binding and G protein Activation in Female Monkeys,” Neuropsychopharmacology 2002;27: 12-24.

44. Clarke WP, Maayani S. “Estrogen effects on 5-HT1A receptors in hippocampal membranes from ovariectomized rats: functional and binding studies,” Brain Res 1990 Jun 4;518(1-2):287-91.

45. Klink R, Robichaud M, Debonnel G. “Gender and gonadal status modulation of dorsal raphe nucleus serotonergic neurons. Part I: effects of gender and pregnancy,” Neuropharmacology 2002 Dec;43(7):1119-28.

46. Robichaud M, Debonnel G. “Oestrogen and testosterone modulate the firing activity of dorsal raphe nucleus serotonergic neurones in both male and female rats,” J Neuroendocrinol 2005 Mar;17(3):179-85.

47. Andréen L, et al. “Pharmacokinetics of progesterone and its metabolites allopregnanolone and pregnanolone after oral administration of low-dose progesterone,” Maturitas 2005, 54(3); 238-244.

48. Marx CE. “Neurosteroids and psychiatric disorders,” Psychiatric Times 2001 Oct; vol XVIII(10).

49. Kaura V, et al. “The progesterone metabolite allopregnanolone potentiates GABA(A) receptor-mediated inhibition of 5-HT neuronal activity,” Eur Neuropsychopharmacol 2007 Jan 15;17(2):108-15.

50. Sinnott RS, Mark GP, Finn DA. “Reinforcing effects of the neurosteroid allopregnanolone in rats,” Pharmacol Biochem Behav 2002 Jul;72(4):923-9.

51. Robichaud M, Debonnel G, “Modulation of the firing activity of female dorsal raphe nucleus serotonergic neurons by neuroactive steroids,” Journal of Endocrinology 2004;182:11-21.

52. Charalampopoulos I, et al, “Dehydroepiandrosterone sulfate and allopregnanolone directly stimulate catecholamine production via induction of tyrosine hydroxylase and secretion by affecting actin polymerization,” Endocrinology 2005 Aug;146(8): 3309-3318.

53. Shen W, et al. “Pregnenolone sulfate and dehydroepiandrosterone sulfate inhibit GABA-gated chloride currents in Xenopus oocytes expressing picrotoxin-insensitive GABA(A) receptors,” Neuropharmacology 1999 Feb;38(2):267-71.

54. Robichaud M, Debonnel G. “Oestrogen and testosterone modulate the firing activity of dorsal raphe nucleus serotonergic neurones in both male and female rats,” Journal of Neuroendocrinology 2005;17(3):179-185.

55. Landrigan PJ (ed.) “Chemical Contaminants in Breast Milk,” Environmental Health Perspectives 2002 June; 110(6):A313-A315.

56. Bruinsma KA, Taren DL. “Dieting, essential fatty acid intake, and depression,” Nutrition Rev 2000;58(4):98-108.

57. Hibbeln JR. “Fish consumption and major depression,” Lancet 1998;351(9110):1213.

58. Logan A. “Neurobehavioral aspects of omega-3 fatty acids: possible mechanisms and therapeutic value in major depression,” Altern Med Rev 2003;8(4):410-425.)

59. Mamalakis G, Tornaritis M, Kafatos A. “Depression and adipose essential polyunsaturated fatty acids,” Prostaglandins Leukot Essent Fatty Acids 2002;67:311-318.

60. Mischoulon D, Fava M, “Docosahexanoic acid and omega-3 fatty acids in depression,” Psychiatr Clin North Am 2000;23:785-794.

61. Puri BK, Counsell SJ, Hamilton G, et al. “Eicosapentaenoic acid in treatment-resistant depression associated with symptom remission, structural brain changes and reduced neuronal phospholipid turnover,” Int J Clin Pract 2001;55:560-563.

62. Allport S. The Queen of Fats: Why Omega-3s Were Removed From the Western Diet and What We Can Do To Replace Them, University of California Press, Berkeley, CA: 2006.

63. Kendall-Tackett K. “A new paradigm for depression in new mothers: the central role of inflammation and how breastfeeding and anti-inflammatory treatments protect maternal mental health,” Int Breastfeed J 2007;2.

64. Stoll A. The Omega-3 Connection, Free Press, New York, NY: 2002

65. Halama P. “Efficacy of the Hypericum extract LI 160 in the treatment of 50 patients of a psychiatrist,” Nervenheilkunde 1991;10:305-7.

66. Hansgren D, Vesper J, Ploch M. “Multicenter double-blind study examining the antidepressant effectiveness of the hypericum extract LI 160,” J Geriatr Psychiatry Neurol 1994 (7 Suppl 1):S15-8.

67. Harrer G, Hubner WD, Podzuweit H. “Effectiveness and tolerance of the hypericum extract LI 160 compared to maprotiline: a multicenter double-blind study,” J Geriatr Psychiatry Neurol 1994 (7 Suppl 1);S24-8.

69. Hubner WD, Lande S, Podzuweit H. “Hypericum treatment of mild/moderate depressions with somatic symptoms,” J Geriatr Psychiatry Neurol 1994 (7 Suppl 1):S12-4.

70. Kasper S, et al. “Superior efficacy of St John’s wort extract WS® 5570 compared to placebo in patients with major depression: a randomized, double-blind, placebo-controlled, multi-center trial,” BMC Med 2006.

71. Vorbach EU, Hubner WD, Arnoldt KH. “Effectiveness and tolerance of the Hypericum extract LI 160 in comparison with imipramine: randomized double-blind study with 135 outpatients,” J Geriatr Psychiatry Neurol 1994 (7 Suppl 1);S19-23.

72. Morrazzoni P, Bombardelli E. “Hypericum perforatum,” Fitoterapia 1995;66:43-68.

73. Baldessarini RJ. “Neuropharmacology of S-adenosyl-L-methionine,” Am J Med 1987 (Suppl 5A);83:95-103.

74. Bottiglieri T, et al. “Cerebrospinal fluid S-adenosylmethionine in depression and dementia: effects of treatment with parenteral and oral S-adenosylmethionine,” J Neurol Neurosurg Psychiatry 1990;53(12):1096-8.

75. Bottiglieri T. “Ademetionine (S-adenosylmethionine) neuropharmacology: implications for drug therapies in psychiatric and neurological disorders,” Expert Opin Investig Drugs 1997;6(4):417-26.

76. Kagan BL, et al. “Oral S-adenosylmethionine in depression: a randomized, double-blind, placebo-controlled trial,” Am J Psychiatry 1990;147:591-595.

77. Mischoulon D, Fava, M. “Role of S-adenosyl-L-methionine in the treatment of depression: a review of the evidence,” Am J Clin Nutr 2002 Nov;76(5): 1158S-1161S.

78. Rosenbaum JF, et al. “The antidepressant potential of oral S-adenosyl-l-methionine,”Acta Psychiatrica Scandinavica 1990 May;81(5):432-436.

79. Bersudsky Y, et al. “Epi-inositol and inositol depletion: two new treatment approaches in affective disorder,” Curr Psychiatry Rep 1999 Dec;1(2):141-147.

80. Belmaker, R. H. et al. “Manipulation of inositol-linked second messenger systems as a therapeutic strategy in psychiatry,” Adv Biochem Psychopharmacol 1995;49: 67-84

81. Benjamin J, et al. “Double-blind, placebo-controlled, crossover trial of inositol treatment for panic disorder,” Am J Psychiatry 1995;152 (7):1084-6.

82. Palatnik A, et al. “Double-blind, controlled, crossover trial of inositol versus fluvoxamine for the treatment of panic disorder,” J Clin Psychopharmacol 2001;21(3): 335-339.

83. Fux M. “Inositol treatment of obsessive-compulsive disorder,” Am J Psychiatry 153(9): 1219-1221.

84. Colodny L, Hoffman RL. “Inositol-clinical applications for exogenous use,” Altern Med Rev 1998;3(6):432-47.

85. Levine J, et al. “Double-blind, controlled trial of inositol treatment of depression,” Am J Psychiatry 1995;152(5):792-794.

86. Levine J. “Controlled trials of inositol in psychiatry,” Eur  Neuropsychopharmacol 1997;7(2):147-55.

87. Levine J, et al. “Combination of inositol and serotonin reuptake inhibitors in the treatment of depression.” Biol Psychiatry 1999;45(3): 270-273.

88. Nathan PJ, et al. “The neuropharmacology of L-Theanine(N-Ethyl-L-Glutamine): a possible neuroprotective and cognitive enhancing Agent,” Journal of Herbal Pharmacotherapy: Innovations in Clinical and Applied Evidence-Based Herbal Medicinals 2006; 6(2).

89. Mason R. “200 mg of Zen; L-theanine boosts alpha waves, promotes alert relaxation,” Alternative & Complementary Therapies 2001 Apr 7:91-95.

90. Nagasawa K, et al. “Possible involvement of group I mGluRs in neuroprotective effect of theanine,” Biochem Biophys Res Commun. 2004 Jul 16;320(1):116-22.

91. Blum J et al., “A randomized double-blind clinical trial investigating fourteen postpartum symptoms comparing After Baby Boost comprehensive postnatal nutritional system vs. a leading prenatal vitamin as placebo.”