The Assitant's of Krebs

Learn which minerals, vitamins and amino acids are involved in the Krebs cycle and their functions

Depression: Allopathic Approach and Physiology

On my previous blog I explained how different nutrients elicit changes in the brain structure and neuronal transmission. This blog is intended to explain what is monoamine oxidase (MAO), what are monoamines, from which amino acid(s) the neurotransmitter(s) are synthesized, the functions of those neurotransmitters, the consequences of having deficiency of those neurotransmitters and the allopathic approach for treating depression and an explanation of why we observe certain side effects on certain drugs. It is my intention to give an idea of the physiological alterations created by these medications. Please bear in mind that this information it is limited and its purpose is to educate.
The references used for this blog and others are in the form of links.

Monoamine Oxidase

Monoamine Oxidase is an enzyme that catabolizes monoamines. Monoamines are serotonin, dopamine, epinephrine, norepinephrine, GABA, melatonin, and histamine; yes, the term monoamines refers to neurotransmitters that have one amino acid group hence mono (meaning one) and amine (from the term referring to the origin of the amino acid: ammonia).
There are two types of Monoamine Oxidase: MAO-A and MAO-B.
MAO-A brakes down serotonin, norepinephrine and epinephrine while MAO-B mainly catabolizes phenethylamine. Dopamine is broken down by MAO-A and MAO-B.

Role of Monoamines

Dopamine:  execution on movement, inhibition of prolactin, memory, attention, problem solving and other neuro-cognitive functions, motivation, pleasure, and reward seeking behavior.  
Synthesis: phenylalanine.

Serotonin: regulation of insulin and Insulin like Growth Factor (IGF), serotonin effects appetite, sleep, and general metabolism, and blood vessel constriction. Modulates mood, anger and aggression. Stimulates cells to repair the liver and promotes osteoclasts activity.  
Synthesis: tryptophan.

Epinephrine(adrenaline):  It is involved in the fight-flight response: increases blood perfusion to the brain and skeletal muscles and diminishes blood supply to the GI tract. Suppresses the immune system and elevates blood sugar and breaks down lipids in cells.  
Synthesis: phenylalanine.

Norepinephrine (noreadrenaline):  involved in the fight-flight response. Increases blood pressure and
drops heart rate.  
Synthesis: Dopamine which in turn is made from phenylalanine.

GABA:  Regulates neuronal excitability and muscle tone.  
Synthesis: Glutamate.

Histamine:  Regulates sleep, is involved in inflammation and immune responses, has erectile and sexual functions. Protect against convulsion, stress, and ischemic lesions.  
Synthesis: histidine.

Melatonin:  antioxidant (mainly protects nuclear and mitochondrial DNA), regulates circadian rhythms. Enhances immune functions.  
Synthesis: Tryptophan.

Phenethylamine:  Acts as a releasing agent of dopamine and norepinephrine.  
Synthesis: Phenylalanine.

Amino Acids Deficient in Depression

It is of common knowledge that dopamine and serotonin are the main neurotransmitters affected in people with depression. If we take a closer look to the previous list of monoamines and their functions it will be noticed that phenylalanine and tryptophan are deficient in patients with depression; these amino acids are also essential for the synthesis of other neurotransmitters: Melatonin, Phenethylamine,Norepinephrine, and Epinephrine .
It is not surprising to see a big conglomerate of signs and symptoms in people with depression: insulin resistance, high levels of homocysteine, interlukin and tumor necrosis factor besides the well known signs and symptoms of apathy, sadness, emptiness, guilt, feeling of worthlessness, polyphagia or decreased appetite, insomnia or excessive sleeping, impaired immunity, and decreased libido among others sexual problems.

Allopathic Approach to Depression

The conventional approach to depression is the use of the following medications MAOI (Monoamine Oxidaze Inhibitor) SSRI (Selective Serotonin Reuptake Inhibitor), TAC (Tricyclic Antidepressants), Tetracyclic Antidepressants (Tricyclic and Tetracyclic are known as heterotricyclic),  Serotonin Modulators (5-HT2 Blockers), Norepinephrine-Dopamine Reuptake Inhibitors (NDRI), and SNRI (Serotonin-Norepinephrine Reuptake Inhibitor) and Electroconvulsion Therapy.


List of Medications

Heterocyclic Antidepressants:  amitriptyline, amoxapine, clomipramine, desipramine, doxepin, imipramine, 
maprotiline, nortryptiline, protriptyline, and trimipramine.

Selective Serotonin Reuptake Inhibitors:   citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline.

Monoamine Oxidase Inhibitors:  isocarboxazid, phenelzine, selegiline, tranylcypromine.


Serotonin Modulators:  mirtazapine, nefazodone, trazodone.


Serotonin-Norepinephrine Reuptake Inhibitors:  duloxetine, venlafaxine, desvenlafaxine


Norepinephrine-Dopamine Reuptake Inhibitors:  bupropion.




The Logic Behind the Medications

TAC:  This medications inhibit the reuptake of serotonin and norepinephrine by blocking the serotonin and 
norepinephrine transporter (SERT and NET respectively) which in turns increases the levels of serotonin and norepinephrine. The higher the level of serotonin the lower the level of melatonin and viceversa, usually melatonin increases while serotonin decreases: melatonin is metabolized from serotonin. Insulin and serotonin increase accordingly: higher levels of serotonin means higher levels of insulin. Insulin is required in order to increase bio-availability of tryptophan; the downfall is that it might cause insulin resistance which leads to diabetes. An analysis of the functions of melatonin and serotonin will make evident that this medication will cause an imbalance on the circadian rhythms, an increase on blood pressure, GI tract disorders; because norepinephrine activates fight-flight response a reduction on blood flow to the GI tract will be observed leading to slow metabolism and absorption of nutrients from the GI tract leading to poor nutrient assimilation and weight gain. Norepinephrine increases blood flow to the brain which explains why people suffer from blurred vision and dizziness when taking TAC's. Muslce stiffness and twitches are present: remember this medication activates the fight-flight response making  the muscles the primary target.
Cyclics effect every receptor in the CNS which includes Histamine and Muscarinic receptors among others.

              Some TAC's medications are: Anafranil, Adapin, Aventyl, Elavil, Norpramin, Pamelor, Pertofrane, Sinequan, Surmontil, Tofranil, and Vivactil.

MAOI:  There are 3 types known, the one that does not discriminate and inhibits MAO-A and MAO-B and  those that do discriminate and only inhibit MAO-A or MAO-B. MAOIs work by inhibiting the             production of monoamine oxidase which catabolizes serotonin, epinephrine, norepinephrine and dopamine with the aim of increasing blood levels and make them bioavailable. The problem with MAOI is that they increase tyramine levels in the blood. Tyramine is synthesize from Tyrosine. Tyramine acts as a releasing agent of dopamine, epinephrine, and norepinephrine. An increase in tyramine means an increase on dopamine, epinephrine and norepinephrine therefore we will see similar side effects as with TAC's. Consumption of tyrosyne containing food will elicit the "cheese effect" where the person will have high blood pressure, headaches, and racing heart. This medication and the TAC are used as a last results due to the severe side effects.
             Some MAOI medications are: Parnate, Nardil, and Marplan.

SSRI:  This medication selectively inhibits the reuptake of serotonin. The side effects are logic: serotonin is
involved in the appetite, sleep, and general metabolism, and blood vessel constriction. Modulates mood, anger and aggression. Stimulates cells to repair the liver and promotes osteoclasts activity. An increase on serotonin means an effect on any of the functions it regulates.
According to the Journal of Psychopharmacology Jan 1998; vol. 12: pp. 396 - 400: SSRI's cause hyponatremia which is an imbalance
of the sodium electrolyte(calcium, chloride, magnesium and potassium are the most common electrolytes in the human body besides sodium). This sodium imbalance can cause headache, fatigue,  weakness and nausea as first symptoms. More severe cases can result in confusion, seizure, coma and death. This sodium imbalance might explain why patients get headaches, fatigue, weakness or nausea when taking SSRI.  Low sex drive and inability to experience orgasm or retardation of ejaculation are other symptoms which are due to their effect of different type of serotonin receptors (each receptor has effects and affects different physiological aspects of the human body).
           Some SSRI medications are: Celexa, Lexapro, Luvox, Paxil, Prozac and Zoloft.

SNRI:  Increases amount of serotonin and norepinephrine in the synaptic gap. At this point we should have
an idea of the possible side effects of this type of medication based upon the functions of serotonin and  norepinephrine. I must add that the last 2 medications SSRI and SNRI are the most safest of all but that does not mean that side effects are absent. According to WebMD the side effects are the following: weight loss, decreased appetite, restlessness, insomnia, anxiety, constipation, dry mouth, diarrhea, dizziness, drowsiness, blurred vision, light headedness, strange dreams, constipation, fever/chills, headache, increased or decreased appetite, tremor, dry mouth, nausea. Many of these signs and symptoms can be explained to the activation of the fight-flight response while others are related to the close relationship with dopamine and its interaction with other hormones and body processes (ie activation of other serotonin receptors:  S1,S2,etc)
           Some SNRI medications: Effexor, Remeron, and Cymbalta.

DNRI :  Dopamine-Norepinephrine Reuptake Inhibitors functions are obvious: they slow down the reabsorption of dopamine and norepinephrine allowing more concentration of the neurotransmitters. The possible side effects are obvious if we look for the functions of these 2 neurotransmitters. This medication has been linked to seizures (JAOA Vol 7. NO10. October 2007 p 441).
There are different types of DNRI: immediate release (IR), extended release (ER) and sustained release (SR).
           Some DNRI medications:  Bupropion ER, Bupropion IR, Bupropion SR.

 ECT:  Electroconvulsion Therapy is used when everything has fail; occurrence of relapse is possible.
Electroconvulsion as the name implies is the use of electrodes placed on the head to elicit seizures;
anesthesia is provided to the patient due to muscle contractions experienced during the treatment.
Possibility of  memory loss.

OTHER EFFECTS

Other effects that some antidepressant medications exert in the body is the suppression of CYP450. CYP450 is the generic name given to a group of more than 50 enzymes found in the lungs, small intestine, liver and kidneys. These enzymes are involved in the synthesis of several hormones (i.e. estrogen, testosterone), bile acids, cholesterol, thromboxane A2 and metabolism of fatty acids, degradation of vitamin D and the elimination of toxins of the body via the urine and stools. A decrease function of CYP450 can elicit a cascade of effects in our body: high cholesterol, low levels of sex hormones, poor fatty acids metabolism and many others. If we incorporate genetic determination we will notice that some patients have less active CYP450 versus others that have highly active CYP450 then it will be obvious that for some patients the side effects will be more pronounced than others. These patients with a higher CYP450 activity are referred as having "wild" CYP450.

 STATISTICS

According to the newspaper Acupuncture Today December 2001 Volume 2 Issue 12 there are over 28 millions Americans taking antidepressants and anti-anxiety medications but more astonishing is what Merck Manual for Medical Conditions have to say about the efficacy of these medications : "...The chances that any given antidepressant will work for a particular person are about 65%..."
In other words there is a 35% chance that the medication will not work which makes it a big portion of patients that are still affected.
For that reason we are in our right to ask: Is there any alternative for these non-reactive patients?
The answer is yes! and in a next blog I will examine herbal medicine and acupuncture as an alternative.

 

 

Depression and the Role of Nutrients in Our Diet

Over 28 millions Americans are taking antidepressants and anti-anxiety medications. It is speculated that for 2020 depression would be the second cause of disability in Western Countries or Industrialized countries.

The question that comes to our mind is why industrialized countries are having such a increase on depression? Is there something more that is escaping to our big picture?

What is Depression?

It is well known that depression is the result of problems with neurotransmitters or neuro-transmission. The criteria commonly used to diagnosed depression is summarized by SIGECAPS which stands for:

Sleep: Insomnia or hypersomnia is present in a daily basis

Interest: a noticeable lack of interest on activities that were delectable and amusing to the patient

Guilt: the presence of disproportionate guilt and/or worthlessness

Energy: reduce or lack of energy, fatigue. Decrease libido

Concentration: Thinking and concentrating are significantly altered or diminished. The presence of indecision 
                       is accentuated.

Appetite: hyperphagia or hypophagia (increased or decreased appetite)

Psychomotor: agitation or retardation of psychomotor processes

Suicide: Recurrent thoughts of death/suicidal thoughts

In order to be diagnosed with depression the patient must be feeling empty, sad or with loss of interest for 2 weeks plus 4 or more of the above criteria. In addition, the "sadness" should create a significant impairment in social, occupational or other areas of his/her life.

Brain Anatomy and Chemistry

After taking all the fluid content out of the brain what we have left is 60% of fat where 20% is composed of polyunsaturated fats known as Omega-3 and Omega-6. From Omega-3 Fatty Acids (FA) we obtain EPA and DHA which play a significant role on the structure of neurons (DHA) and neural transmission (EPA).

 The brain protects itself from toxin by means of methylation. This process enables the creation, reparation and maintenance of neurons and neurotransmitters; homocysteine has been linked with the suppression or retardation of methylation.

Amino acids are needed for the creation of neurotransmitters while  vitamins and minerals are important in facilitating the creation of them by acting as catalysts.

The brain uses 500 grams of healthy carbohydrates as energy source.

When we analyze these facts we can't help to realize that amino acids, vitamins, minerals, carbohydrates and fats are all important in the proper function of the brain. 

Nutrional Deficiencies in Depression

It has been found that people that suffer from depression lack or are deficient of: selenium, zinc, magnesium, vitamin c, vitamin b complex, folic acid, omega-3 and amino acids such as tryptophan, and phenylalanine .

It is important to point out that reasearch and studies have linked a low consumption of fish with an increase on depression.


Amino Acids and Depression
 
Some amino acids linked with depression are Dopamine and Serotonin which give rise to Melatonin, Phenethylamine,Norepinephrine, and Epinephrine.

Amino Acids and the pH

The pH plays a very important role on what is called protonation and deprotonation which simply means that a molecule has accepted or given away a hydrogen...Amino acids have an area that is called functional group which is the one capable of interacting with other molecules. A well balanced pH will help the proper chemical reactions.
It is important to understand that amino acids are divided in 4 different groups: hydrophilic, hydrophobic, acidic and basic (alkaline). Hydrophilic substances are "water loving" and dissolve easily in water while hydrophobic molecules are "water hating substances" and by deduction they do not dissolve in water but in other substances like fat. Chemical reaction relies heavily in a well sustained pH.
The amino acids that are hydrophobic are the following: Alanine, Valine, Leucine, Isoleucine, Proline, Methionine, Phenylalanine and Tryptophan. Tryptophan is a special case, it interacts with water in a very limited range.  Hydrophilic amino acids are: Glycine, Serine, Asparagine, Glutamine, Threonine, Tyrosine, and Cysteine.
Basic amino acids are: Histidine, Arginine, and Lysine. Acidic amino acids are: Aspartic acid and Glutamic acid.
In order for these amino acids to interact with other molecules the body needs a sustained and ideal pH.


The Forgotten Universal Key Ingredient
 

We have to consider the following facts: 70% of the human body is water while at the cellular level 60 - 90% is water; 55% of that water is found on intracellular fluids while the remaining 45%  is found on extracellular fluid: 8% in plasma, 22 % on interstitial and lymph, and 15% in connective tissue, cartilage and bone.Our cells use water to dispose of waste, as transportation of substances in and out of the cell, to regulate temperature and to carry nutrients through out the body.
As we can see water is a very important factor in order to have and keep a healthy diet.

How Much Water?

First we have to bear in mind the following physiological evidence:  healthy humans (note that healthy is in bold which means that people that are not healthy might need more) loss approximately 2 liters of water per day of that amount 50% is loss via urine while 5% is lost in fecal matter the remaining 45% is lost through our lungs and skin; for that reason we need 'healthy' fresh fruits and vegetables to replenish as much as possible that water lost.
As a rule of thumb I always advice to drink 2 glasses of water as soon as you wake up and one glass of water 30 minutes to 1 hour after having a meal or snack by doing so you can rest assure that you keep your cells well hydrated and equipped to transport nutrients, hormones, other substances and the proper methylation process.

What to Avoid

Avoid the consumption of hydrogenated oils, refined carbohydrates and process food. 

What to Eat

Increase the consumption of fresh vegetables, fruits, seafood and unprocessed carbohydrates.

The Modern Dilemma of Eating Healthy

The problem we are facing is vast: our farming methods have changed significantly in such way that cattle is been fed grains (or other food) instead of grass, which causes a decrease in Omega-3 ; the same problem goes with chicken and fish. Our soil is less saturated with minerlas due to our farming methods. The increase use of pesticides and herbacides has caused our food to be polluted; it has been found bread with residue of pesticides.

The food we eat has been loaded with dozen of additives which exert a biochemical interaction  at a cellular level; this includes the brain.

The food supply of industrialized countries is so high on Omega-6, sugar, salt and hydrogenated fats that it has been observed that people suffering depression have insulin resistance,  higher levels of interlukin 1 beta, homocysteine, tumor necrosis factor alpha and prostaglandin E2.

What Else Can We Do?

It has been noticed that aerobics, cardiovascular exercises, yoga, meditation,  and acupuncture can impact depression significantly.

 We can improve our health by eating organic food or food that has not been chemically treated.

The Codex Alimentarius and Us

Codex Alimentarius is supposed to be a set of regulations to safeguard our food supply; the only problem is that codex alimentarius contemplates the use of radiation in every food including organic. Not only that, Codex Alimentarius sees as dangerous the use of vitamins, minerals and other supplements as alternative therapy hence it has been proposed to cut by more than 50% the recommended daily allowance that we have in our food supply as of 2009 and prior. Starting in 2010 Europe will be implementing the Codex Alimentarius which means that any food will have less vitamins, minerals etc that it is nowadays. Even more by radiating our food supply we will have no nutrients left in our breakfast, lunch and dinner.