Antidepressants have a role in clinical practice but they are grossly over-utilized.  As a certified psychopharmacologist, practitioner of Whole Psychiatry (Functional Medicine and traditional psychiatry) and Clinical Professor of Psychiatry at Georgetown School of Medicine, I prescribe antidepressants, but  only after a thorough multi-faceted  evaluation of the patient.

We rely on drugs as a solution rather than deal with root causes of illness, and the pills generally are not as effective as we would be led to believe by the pharmaceutical companies (publically acknowledged as distorted in peer reviewed journals such as New England Journal of Medicine, Eric Turner, 2008). Nor are these drugs without financial costs and side effects.  I suggest that the solution is to develop better assessments of the metabolic factors leading to the syndrome of depression. The psycho-social-spiritual risk factors are reasonably well spelled out, and we have excellent targeted psychotherapeutic techniques available now.

The fact that the head and brain are connected to the body by something called the neck may be relevant.  In fact, there is a great deal of basic science and a good deal of clinical science indicating the very significant role played in subjective and objective mental health by at least six metabolic systems: nutrition, gastrointestinal physiology, immune/inflammatory/infectious processes, methylation processes, oxidative stress, and all hormonal systems.  This list excludes other factors such as circulatory problems, physical-structural problems, age, gender, and lifestyle factors.

Assessing these metabolic systems, and their mediators in a careful comprehensive manner, and re-establishing multi-system reserves not only helps depression with less medication, but at the same time reduces the side effect burden imposed by medication, and reduces the incidence of known co-morbidities such as diabetes, cardiovascular disease, osteoporosis, sexual dysfunction.  Psychopharmacology is only one small tool in our toolbox.  As Confucius once said, “To do good work, one must first have good tools.”  Anti-depressants are somewhat useful tools; they are just not the best or the only ones.  We have other tools at our disposal.  Why not use them?

I was wandering around the internet last night, looking for scholarly articles on something called ‘methylation pathways’, when I came across a very disturbing article on the potentially quite toxic interaction between nitrous oxide (NO2) and certain states of B12 deficiency. Before getting into the nitty gritty, bottom line, let me give you some background.

Nitrous Oxide (NO2)-commonly referred to as ‘laughing gas’ was used for years in the practice of dentistry.  It is used currently as part of general anesthesia, and recently has been gaining popularity as a ‘recreational drug’.  An article in Popular Science in the late 1940’s demonstrates how easy it is to make NO2 with an at ‘home laboratory’.

The methylation pathway I refer to above is a fundamental biochemical pathway occurring billions of times per second in the human body.  It’s like the dollar bill of our economy-it keeps things moving.  Methylation plays a key role in the building up and breaking down of molecules.  For example, methylation helps make and break down neurotransmitters (serotonin, dopamine, norepinephrine), estrogens, and histamine (think allergy); methylation helps turn certain genes on and others off, and methylation is involved in protecting nerve cells, making blood cells, strengthening collagen (fewer wrinkles), etc.

The methylation pathways work well when we get enough B12 in our diet (vegans are very vulnerable to B12 deficiencies), enough folic acid (spinach, kale, Swiss chard), and B6.  Additionally selenium (nuts), vitamin B2 (riboflavin), magnesium (Brazil nuts and almonds), and some amino acids (methionine, cysteine, serine, glycine, taurine) are needed to keep the methylation cycle running smoothly.

In addition to these nutrients, we must have genes that can make the enzymes that ‘grease the wheels’ of these pathways.  These enzymes allow things to flow smoothly, and allow methylation to meet the demands of the body and environment.  There are several genes involved in the methylation pathways, and abnormalities of one or more of these genes are quite common (e.g., MTHFR C677T).  These abnormalities slow down the methylation pathways, and connected detoxification and free-radical pathways.

So here is the punch line:

Laughing gas (N02)―nitrous oxide―stops the methylation pathway in its tracks by deactivating B12, and stopping the activity of a certain enzyme for days to weeks. When someone is already deficient in B12/folate (e.g., due to diet, medications such as proton pump inhibitors or Metformin),  or has genes that are not functioning properly, the B12 deficiency is suddenly worsened, and weeks later neurological and psychiatric problems develop. They can be subtle (e.g., trouble with balance) or they can be severe (cognitive problems); any psychiatric syndrome (e.g., panic, depression) can develop.  It is unlikely that anyone will make a correlation of cause and effect between the NO2 and the symptoms, because of the delayed toxicity, and the fact that not every one is effected. Symptoms can be subtle.

NO2 is a very serious danger to your health. The risk is unappreciated by college students who are using NO2 as a recreational drug, and the risk needs to be assessed before use of anesthesia (by testing homocysteine and methionine in the blood, looking for risk factors for B12 deficiency such as a vegan diet or the use of certain medications, as well as the genetic MTHFR test) when possible.  Please raise people awareness of this risk by passing this information along.

Yes!  Over the last 20 years, ample evidence has accumulated to prove that inflammation in the body causes changes in the brain that lead to depression, anxiety, sleep problems, and memory problems. Inflammation comes from the Latin  ‘inflammare’ -- to set on fire.  Our brain is ‘on fire’ when it is inflamed, or when our body is inflamed.

What sets your brain on fire?

Your body experiences inflammation the way your skin reacts to a cut:  The area becomes swollen, warmer, and it may hurt.  (This happens because there is increased blood flow, increased immune activity, and a change in the chemistry in the area.)

When there is inflammation any where in the body, signals are sent to the brain via various cytokines. The cytokines send signals to the brain via the vagus nerve and other pathways.  These cytokine signals then block the brain from making serotonin.

What does the fire do to your brain?

Inflammation affects hormones and other neurotransmitters in your brain. Inflammation drives down the level of serotonin, which can lead to feelings of depression or anxiety, and problems with memory.  It prevents melatonin from being produced, which causes insomnia.  It causes dopamine levels to rise, which contributes to insomnia, and feelings of anxiety and agitation.  The excitatory neurotransmitter, glutamate, goes up. Over time or with excessive levels of glutamate, anxiety can result. In extreme amounts, glutamate can be toxic to brain cells.

In fact, in depression, a certain type of brain cell-called an astrocyte, actually deteriorates under these circumstance, which permits the inflammation to continue. Now you have a brain that is, if not on fire, at least smoldering.

You too can prevent brain fires!

It’s not as complicated as you might think!  Try these suggestions (with your doctors approval of course.)

A) Clean up your diet by eliminating food common allergies –

¨    breads

¨    gluten

¨    milk and dairy products

¨    eggs 

¨    sugar

B) Balance your diet

¨    Try the Barry Sear’s “Zone” diet, or one of the diets in my book-“The Anti-depressant Survival Guide”

C) Keep exercise moderate,

D) Make sure your air is clean

¨    No mold, or things you are allergic to-such as dust mites

E) Reduce your stress so your adrenal glands can recover their anti-inflammatory function

F) Clear up all gut issues

¨    70% of inflammation comes from the gut-such as bloating, gassiness, diarrhea, constipation and reflux.

G) Be sure you do not have any hidden infections.

H) Drink lots of water

I) Eat lots of anti-oxidant rich foods

¨    Lots of organic colorful veggies, with a bit of fruit

Nutrition, Detoxification, and Depression
An additional avenue through which nutrition can help mood disorders is via liver detoxification, which can influence mood via the modification of steroid hormone metabolism (e.g., DHEA, testosterone, estrogen, cortisol). 

Detoxification occurs in two phases:  In phase one the CYP 450 enzymes are supported by a variety of nutrients (B2, B3, B6, folic acid, B12,Glutathione, branched-chain amino acids, flavinoids, phospholipids). Once these CYP450 enzymes have acted on the lipid soluble molecule, (drug, hormones, toxins), by adding an oxygen, these activated intermediates, (if not further detoxified via phase two, due to nutritional deficiency) can increase oxidative stress, and via mitochondrial damage, reduce neuronal function.  Phase two conjugation pathways require glutathione, glycine, taurine, glutamine, ornithine, arginine, N-acetylcysteine, cysteine, methionine, selenium.  If phase two conjugation is  functioning well, the substances are rendered water soluble and can pass out of the body via the kidney, or bile (where in the presence of dysbioisis they may be re-absorbed if cleaved in the intestine [soluble fiber helps to counter this]).

Failure to detoxify steroid hormones, such as estradiol, can alter the synaptic availability of neurotransmitters, thereby affecting mood disorders. Failure to detoxify endocrine disrupting chemicals (e.g., PCB’s, BPA) will adversely affect mood disorders by altering normal endocrine function, which is necessary for normal brain function.

Nutritional Balance and Depression
Finally, we must look at the macronutrient aspect of the diet.  Meals must be balanced in protein (1/3 of the meal volume) and complex carbohydrates (2/3 of the meal volume).  This will keep blood sugar steady, eliminating the significant dysglycemic contribution to intra-day mood swings, irritability, and anxiety. Along these lines, it is important that the clinician manage insulin resistance and diabetes via diet, exercise, and supportive nutrients such as R-Lipoic Acid, chromium, vanadium. Van Praag (14) demonstrated that “50% of depressed patients had lower glucose utilization during a glucose tolerance test than did control subjects.” Furthermore, Cassidy (15) demonstrated that manic-depressive patients with diabetes mellitus (n=357) have a more severe course of illness, as indicated by a greater number of psychiatric hospitalizations (p=<0.05).

Summary
Based on this quick overview, it should be clear that adequate and individualized nutritional assessment and intervention is a cornerstone of appropriate treatment of mood disorders.  Failure to utilize this basic information accounts for a significant component of treatment resistant depression, medication failure, and polypharmacy.

References:
1)  Rush, AJ. STAR-D: What have we learned? Am J Psychiatry. 2007;164-201
2)  Pigott, et al. Efficacy and Effectiveness of Antidepressants: Current Status:Psychother Psychosom. 2010;79(5):267-79.
3)  Bourre, JM: J. Nutrition, Health & Aging: Vol 10(5) 2006: 377-385. Effects of nutrients (in food) on the structure and function of the nervous system: update on dietary requirements for brain: Part 1: micronutrients.
4)  Miller HL :et al.: Clinical and biochemical effects of catecholamine depletion on antidepressant-induced remission of depression. Arch Gen Psychiatry. Vol.53( 2):117-128.
5)  Spillmann MK. Et.al.; Tryptophan depletion in SSRI recovered depressed outpatients. Psychopharmacology (Berl)2001, May;155 (2):123-127
6)  Maes M.,et al.:Hypozincemia in depression. J Affective Disorders; 31(2):13Maes M.: “Lower serum zinc in major depression is a sensitive marker of treatment resistance and of the immune/inflammatory response in that illness” Biol Psychiatry: 42(5):349-358 (1997).5-140 (1994)
7)  Maes M.Et.al.: Lower serum zinc in major depression in relation to changes in serum acute phase proteins. J. Affect Disord 1999:56(2-3):189-194
8)  Methylenetetrahydrofolate Reductase (MTHFR) Genetic Polymorphisms (C677T variant) and Psychiatric Disorders: A HuGE Review: Am J Epidemiol 2007;165:1–13
9)  Coppen A, et al.: Enhancement of antidepressant action of fluoxetine by folic acid: a randomized, placebo controlled trial. J Affect Disord: 2000:60(Nov.):121-130
10) Rutten: Epigenetic Mediation of  Environmental influences in Major Psychotic Disorders Schizophrenia Bulletin; 2009: Vol 35 (6):1045-1056
11) McGowan: the epigenetics of social adversity in early life: Implications for mental health outcomes. Neurobiology of Disease (2010): In Press
12) Hedelin, M. Dietary Intake of Fish, Omega 3’s, Omega 6 PUFA’s and Vitamin D and the pPrevalence of Psychotic Symptoms in a Cohort of 33,000 Women from the General Population. BMC  Psychiatry 2010 (10): 38; 1-13
13) Wilkins CH., et al.: Vitamin D deficiency is associated with low mood and worse cognitive performance in older adults. Am J Geriatric Psychiatry, 2006 Dec;14(12):1032-40
14) Van Praag: Depression, glucose tolerance, peripheral glucose uptake and their alterations under the influence of anti-depressive drugs of the hydrazine type. Psychopharmacologia (Berlin) 1965;8:67-78.)
15) Cassidy, F. et.al.: Elevated Frequency of Diabetes Mellitus in Hospitalized Manic-Depressive Patients. Am J Psychiatry 1999;156 1417-1420.  
16) Weiss JH., et.al.: Zn(+2): a novel ionic mediator of neural injury in brain disease. Trends Pharmacol Sci 2001: 21(12):112-3
17) Lindenbaum J. et.al.: Neuropsychiatric disorders caused by cobalamin deficiency in the absence of anemia or macrocytois. N Engl J Med 1988;318:1720-1728.
18) Vogiatzoglou, A. Determinants of Methylmalonic Acid in a Large Population: Implications for Assessment of Vitamin B12 Status. Clinical Chemistry (55)12: 2198-2206 (2009)

Nutrition, Neuronal Protection and Depression
Neuronal protection (protection against cognitive decline) requires glutathione peroxidase (a crucial enzyme which requires selenium, cysteine, carotenoids, zinc,  and vitamin E) is an important aspect of the treatment of mood disorders both because they tend to be recurrent over one’s life, and because they are associated with neuronal loss in specific parts of the brain, such as the hippocampus. R-lipoic acid, vitamin C and omega 3 fatty acids are also critical to neuronal protection.

Omega 3 Fatty Acids, Vitamin D, and Depression

There are numerous studies of the efficacy of omega 3 EFA’s in depression.  A recent large-scale (33,000) cohort of Swedish women (12) found that “a frequent consumption of fish, omega-3 and omega-6 fatty acids appears to reduce the risk of positive psychotic-like symptoms. Interestingly, they found a lower rate of psychotic-like symptoms with increasing vitamin D intake.”  It is unclear what the optimal dose of Omega 3’s is, and while it is thought that EPA is better for mood disorders, this is not clear yet.

In a cross-sectional study (13) of older adults (N=80), vitamin D deficiency was associated with low mood and with impairment on two of four measures of cognitive performance.  After adjusting for age, race, gender, and season of vitamin D determination, vitamin D deficiency was associated with presence of an active mood disorder (p = 0.022).

References:
1) Rush, AJ. STAR-D: What have we learned? Am J Psychiatry. 2007;164-201
2) Pigott, et al. Efficacy and Effectiveness of Antidepressants: Current Status:Psychother Psychosom. 2010;79(5):267-79.
3) Bourre, JM: J. Nutrition, Health & Aging: Vol 10(5) 2006: 377-385. Effects of nutrients (in food) on the structure and function of the nervous system: update on dietary requirements for brain: Part 1: micronutrients.
4)Miller HL :et al.: Clinical and biochemical effects of catecholamine depletion on antidepressant-induced remission of depression. Arch Gen Psychiatry. Vol.53( 2):117-128.
5) Spillmann MK. Et.al.; Tryptophan depletion in SSRI recovered depressed outpatients. Psychopharmacology (Berl)2001, May;155 (2):123-127
6) Maes M.,et al.:Hypozincemia in depression. J Affective Disorders; 31(2):13Maes M.: “Lower serum zinc in major depression is a sensitive marker of treatment resistance and of the immune/inflammatory response in that illness” Biol Psychiatry: 42(5):349-358 (1997).5-140 (1994)
7)Maes M.Et.al.: Lower serum zinc in major depression in relation to changes in serum acute phase proteins. J. Affect Disord 1999:56(2-3):189-194
8) Methylenetetrahydrofolate Reductase (MTHFR) Genetic Polymorphisms (C677T variant) and Psychiatric Disorders: A HuGE Review: Am J Epidemiol 2007;165:1–13
9) Coppen A, et al.: Enhancement of antidepressant action of fluoxetine by folic acid: a randomized, placebo controlled trial. J Affect Disord: 2000:60(Nov.):121-130
10)Rutten: Epigenetic Mediation of  Environmental influences in Major Psychotic Disorders Schizophrenia Bulletin; 2009: Vol 35 (6):1045-1056
11)McGowan: the epigenetics of social adversity in early life: Implications for mental health outcomes. Neurobiology of Disease (2010): In Press
12)Hedelin, M. Dietary Intake of Fish, Omega 3’s, Omega 6 PUFA’s and Vitamin D and the pPrevalence of Psychotic Symptoms in a Cohort of 33,000 Women from the General Population. BMC  Psychiatry 2010 (10): 38; 1-13
13)Wilkins CH., et al.: Vitamin D deficiency is associated with low mood and worse cognitive performance in older adults. Am J Geriatric Psychiatry, 2006 Dec;14(12):1032-40
14)Van Praag: Depression, glucose tolerance, peripheral glucose uptake and their alterations under the influence of anti-depressive drugs of the hydrazine type. Psychopharmacologia (Berlin) 1965;8:67-78.)
15)Cassidy, F. et.al.: Elevated Frequency of Diabetes Mellitus in Hospitalized Manic-Depressive Patients. Am J Psychiatry 1999;156 1417-1420.
16)Weiss JH., et.al.: Zn(+2): a novel ionic mediator of neural injury in brain disease. Trends Pharmacol Sci 2001: 21(12):112-3
17)Lindenbaum J. et.al.: Neuropsychiatric disorders caused by cobalamin deficiency in the absence of anemia or macrocytois. N Engl J Med 1988;318:1720-1728.
18)Vogiatzoglou, A. Determinants of Methylmalonic Acid in a Large Population: Implications for Assessment of Vitamin B12 Status. Clinical Chemistry (55)12: 2198-2206 (2009)

Nutrition, Methylation, and Depression
Nutritional support for the methylation cycle is another area in which nutrition plays a critical role.  The methylation cycle is essential for mental and physical health.  It is critical to the metabolism of catecholamines in the synapse via an enzyme (COMT) as well as the synthesis of ‘depression-relevant’ compounds such as melatonin, myelin basic protein, carnitine, CoQ10, etc.  Methylation is required to inactivate histamine.

Basic nutrients necessary for normal function of this cycle include B12, glycine, serine, activated B6, selenium, cysteine, methionine and folic acid.

Several studies have shown the utility of folic acid as an adjunct to medication use for depression.  In one study (10) the average HAM-D (a standard measure of depression) score decreased from 27 to 7 in those receiving P (fluoxetine) plus F (folic acid), and from 27 to 12 in those on P plus Pl (placebo (p<0.001). Recovery (full) was attained in 73% of the women receiving P +F, but only 47% of those on P + Pl (p<0.06).

A variety of genetic polymorphisms (single nucleotide polymorphisms or SNP’s) exist, which can alter function the methylation cycle.  One important SNP is the MTHFR SNP, which when present in both copies of a persons genes, indicates the need for a special form of folic acid: L-methyl folate (which crosses the blood brain barrier). This gene acts by reducing the function of the methylation cycle-specifically reducing the conversion of 5,10 methyl-tetrahydrofolate to 5-methyltetrahydrofolate.  This reduces the synthesis of methionine (needed for the COMT enzyme, which requires s-adenosylmethionine to function), results in increased homocysteine (a marker of methylation status), and altered (decreased or increased) DNA methylation, leaving certain genes turned on or off, when they should not be. In fact, in a review of 1280 psychiatric cases and 10,429 controls, the odds of having depression was 36% greater if a person had two copies of the MTHFR SNP (8).  This means low levels of available folic acid, in this case for genetic reasons, but in other cases due to medications or diet, increases one’s risk for depression by 36%.

In some fascinating research in the area of epigenetics (epigenetics describes the part of the genome that is modified by experience as well as methylation, acetylation, ubiquitination, phosphorylation) suggests that genes that are turned on or off by one’s environment, one’s diet, by stress, or by one’s experience are transmitted to subsequent generations.  One author suggests that the biological underpinnings of bipolar affective disorder are not primarily genetic, but are epigenetic (10).  Another author  (11) presents data that suggests that the fact that identical twins are not fully concordant for depression may have to do with reduced methylation of the COMT gene may be associated with bipolar disorder and schizophrenia, as only 26-29% of these patients, when compared with controls showed normal methylation of the COMT gene in the pre-frontal cortex.  The environmental exposures at key developmental phases may result in long standing neuro-biological changes leading to pathology.  Direct evidence is limited at this point.

One of the critical ingredients for the methylation cycle is B12.  B12 plays a vital role in the metabolism of fatty acids essential for the maintenance of myelin in the brain. Absorption of B12 requires the secretion from the cells lining the stomach of a glycoprotein, known as intrinsic factor.  The B12-intrinsic factor complex is then absorbed in the ileum (part of the small intestine) in the presence of calcium.

Many physicians think that to assess B12 one must measure B12 levels.  However, it is well-established that B12 levels are not a sensitive marker for adequacy of B12 function (17).  Some people suggest that measuring methylmalonic acid (MMA) is more sensitive.  But at least one study (18) shows that B12 function has a minimal effect on levels of MMA. Assessment of B12 status in practice involves measurement of a number of parameters, including the physical exam (depression, impaired balance, panic, neuropathy) the size of red blood cells (MCV), Hematocrit, homocysteine, and functional immunoassays.

References:
1) Rush, AJ. STAR-D: What have we learned? Am J Psychiatry. 2007;164-201
2) Pigott, et al. Efficacy and Effectiveness of Antidepressants: Current Status:Psychother Psychosom. 2010;79(5):267-79.
3) Bourre, JM: J. Nutrition, Health & Aging: Vol 10(5) 2006: 377-385. Effects of nutrients (in food) on the structure and function of the nervous system: update on dietary requirements for brain: Part 1: micronutrients.
4)Miller HL :et al.: Clinical and biochemical effects of catecholamine depletion on antidepressant-induced remission of depression. Arch Gen Psychiatry. Vol.53( 2):117-128.
5) Spillmann MK. Et.al.; Tryptophan depletion in SSRI recovered depressed outpatients. Psychopharmacology (Berl)2001, May;155 (2):123-127
6) Maes M.,et al.:Hypozincemia in depression. J Affective Disorders; 31(2):13Maes M.: “Lower serum zinc in major depression is a sensitive marker of treatment resistance and of the immune/inflammatory response in that illness” Biol Psychiatry: 42(5):349-358 (1997). 5-140 (1994)
7)Maes M.Et.al.: Lower serum zinc in major depression in relation to changes in serum acute phase proteins. J. Affect Disord 1999:56(2-3):189-194
8)Methylenetetrahydrofolate Reductase (MTHFR) Genetic Polymorphisms (C677T variant) and Psychiatric Disorders: A HuGE Review: Am J Epidemiol 2007;165:1–13
9)Coppen A, et al.: Enhancement of antidepressant action of fluoxetine by folic acid: a randomized, placebo controlled trial. J Affect Disord: 2000:60(Nov.):121-130
10)Rutten: Epigenetic Mediation of  Environmental influences in Major Psychotic Disorders Schizophrenia Bulletin; 2009: Vol 35 (6):1045-1056
11)McGowan: the epigenetics of social adversity in early life: Implications for mental health outcomes. Neurobiology of Disease (2010): In Press
12)Hedelin, M. Dietary Intake of Fish, Omega 3’s, Omega 6 PUFA’s and Vitamin D and the pPrevalence of Psychotic Symptoms in a Cohort of 33,000 Women from the General Population. BMC  Psychiatry 2010 (10): 38; 1-13
13)Wilkins CH., et al.: Vitamin D deficiency is associated with low mood and worse cognitive performance in older adults. Am J Geriatric Psychiatry, 2006 Dec;14(12):1032-40
14)Van Praag: Depression, glucose tolerance, peripheral glucose uptake and their alterations under the influence of anti-depressive drugs of the hydrazine type. Psychopharmacologia (Berlin) 1965;8:67-78.)
15)Cassidy, F. et.al.: Elevated Frequency of Diabetes Mellitus in Hospitalized Manic-Depressive Patients. Am J Psychiatry 1999;156 1417-1420.
16)Weiss JH., et.al.: Zn(+2): a novel ionic mediator of neural injury in brain disease. Trends Pharmacol Sci 2001: 21(12):112-3
17)Lindenbaum J. et.al.: Neuropsychiatric disorders caused by cobalamin deficiency in the absence of anemia or macrocytois. N Engl J Med 1988;318:1720-1728.
18)Vogiatzoglou, A. Determinants of Methylmalonic Acid in a Large Population: Implications for Assessment of Vitamin B12 Status. Clinical Chemistry (55)12: 2198-2206 (2009)

Efficacy and Use of Medications in the Treatment of Depression

It is becoming widely recognized that the current treatment of mood disorders (such as depression), while offering better outcomes than several decades ago, leave much room for improvement. The remission rate at the end of the first phase of the well-publicized STAR-D study (1) was only 25%.

In fact, a recent review of 4 meta analyses of the effectiveness of anti-depressants by PIGOTT(2) found that of the 4041 patients initially started on citalopram in the STAR=D study, (after 4 trials of medication combinations and psychotherapy), only 108 of those who remained in the study for a full 12 months achieved full remission. This suggests that when it comes to antidepressant efficacy, we are looking at a 12- month remission rate of 2.7%. Of course, it’s probable that some of the dropouts from the study had remission, but the numbers are still staggering.

Furthermore, there is a strong trend among psychiatrists to treat patients with multiple medications (using the cancer chemotherapy model of multiple agents with different mechanisms of action).  There is also a growing use of these medications in the pediatric population.  Given the low rate of full recovery and the side effect burden of anti-depressants (e.g., metabolic syndrome, elevated cholesterol, loss of libido, possible osteoporosis), as well as the unknown consequences of long term use of these medications in adults and children, it is clearly incumbent upon practitioners to consider additional avenues of treatment, such as nutritional intervention, immune and gastrointestinal modulation, removal of toxic burden, and endocrine function.

In this 4-part article, we will focus on the rational supporting a nutrition approach to depression, as well as a review of those nutrients.  Bourne (3) provides an in-depth look at the micronutrients required for brain structure and function.

Nutrition, Neurotransmission and Depression

First, as we all know, neurotransmission plays a role in mood. Neurotransmission is a process which is dependent on having adequate ‘ingredients’ to synthesize neurotransmitters (NT’s) such as serotonin (Ser), dopamine (DA), norepinephrine (NE), acetylcholine (Ach), and glutamate (Glu). A partial list of nutrients required for synthesis of NT’s includes amino acids (tryptophan, tyrosine, glutamine), minerals (zinc, copper, iron, magnesium), and B-vitamins (B6, B12, folic acid).

In support of the need for adequate amino acids are a series of tryptophan (4, 5) and tyrosine depletion studies, which show that about 60% of people who have already responded to a serotonin re-uptake inhibitor will relapse when tryptophan is removed from the diet-within 5-6 days. Tryptophan depletion has no effect on responders to buproprion, which acts via NE and DA.  However, these people did relapse within 5-6 days when the building block amino acid for NE and DA (tyrosine) was removed from the diet.
The clinical take away from this is to always make sure serum levels of tryptophan and tyrosine are adequate (unless the patient is suicidal) before using an anti-depressant, or giving up on one. It is important to note that one can be eating plenty of protein, yet because of reduced stomach acid (hypochlorhydria), excessive use of antacids, reduced secretion of pancreatic digestive enzyme, or bacterial overgrowth of the small intestine, one can still be deficient in essential amino acids.

Once we have assembled the necessary ingredients to make NT’s, we must have certain cofactors so that the action of the NT at the receptor is efficient.  Zinc is present in particularly large concentrations in the mammalian brain.  Brain zinc is located in pre-synaptic terminals.  Adequate levels of zinc are necessary for action of synaptic vesicles in some gluatamatergic and serotonergic neurons.  It is released with neural activity probably as a modulator of synaptic transition.  

In teens, during the growth spurt, zinc is taken to the bones for growth, thereby depleting the brain; this reduces serotonin function at the receptor.  Clinically, this will be seen as irritability, depression, acne, and zinc spots (white spots) on nails.  According to Maes (6-8) “lower serum zinc in major depression is a sensitive marker of treatment resistance and of the immune/inflammatory response in that illness.”  Additionally, in animal models of zinc deficiency there is impairment of whole body accumulation of Omega 3 polyunsaturated fatty acids^. (PUFA’s). On the other hand, excess levels of zinc are associated with neuronal loss (9), and zinc levels fluctuate inversely with copper levels.  Because of this, levels need to be monitored.

References:
1) Rush, AJ. STAR-D: What have we learned? Am J Psychiatry. 2007;164-201
2) Pigott, et al. Efficacy and Effectiveness of Antidepressants: Current Status:Psychother Psychosom. 2010;79(5):267-79.
3) Bourre, JM: J. Nutrition, Health & Aging: Vol 10(5) 2006: 377-385. Effects of nutrients (in food) on the structure and function of the nervous system: update on dietary requirements for brain: Part 1: micronutrients.
4)Miller HL :et al.: Clinical and biochemical effects of catecholamine depletion on antidepressant-induced remission of depression. Arch Gen Psychiatry. Vol.53( 2):117-128.
5) Spillmann MK. Et.al.; Tryptophan depletion in SSRI recovered depressed outpatients. Psychopharmacology (Berl)2001, May;155 (2):123-127
6) Maes M.,et al.:Hypozincemia in depression. J Affective Disorders; 31(2):13Maes M.: “Lower serum zinc in major depression is a sensitive marker of treatment resistance and of the immune/inflammatory response in that illness” Biol Psychiatry: 42(5):349-358 (1997). 5-140 (1994)
7)Maes M.Et.al.: Lower serum zinc in major depression in relation to changes in serum acute phase proteins. J. Affect Disord 1999:56(2-3):189-194
8)Methylenetetrahydrofolate Reductase (MTHFR) Genetic Polymorphisms (C677T variant) and Psychiatric Disorders: A HuGE Review: Am J Epidemiol 2007;165:1–13
9)Coppen A, et al.: Enhancement of antidepressant action of fluoxetine by folic acid: a randomized, placebo controlled trial. J Affect Disord: 2000:60(Nov.):121-130
10)Rutten: Epigenetic Mediation of  Environmental influences in Major Psychotic Disorders Schizophrenia Bulletin; 2009: Vol 35 (6):1045-1056
11)McGowan: the epigenetics of social adversity in early life: Implications for mental health outcomes. Neurobiology of Disease (2010): In Press
12)Hedelin, M. Dietary Intake of Fish, Omega 3’s, Omega 6 PUFA’s and Vitamin D and the pPrevalence of Psychotic Symptoms in a Cohort of 33,000 Women from the General Population. BMC  Psychiatry 2010 (10): 38; 1-13
13)Wilkins CH., et al.: Vitamin D deficiency is associated with low mood and worse cognitive performance in older adults. Am J Geriatric Psychiatry, 2006 Dec;14(12):1032-40
14)Van Praag: Depression, glucose tolerance, peripheral glucose uptake and their alterations under the influence of anti-depressive drugs of the hydrazine type. Psychopharmacologia (Berlin) 1965;8:67-78.)
15)Cassidy, F. et.al.: Elevated Frequency of Diabetes Mellitus in Hospitalized Manic-Depressive Patients. Am J Psychiatry 1999;156 1417-1420.
16)Weiss JH., et.al.: Zn(+2): a novel ionic mediator of neural injury in brain disease. Trends Pharmacol Sci 2001: 21(12):112-3
17)Lindenbaum J. et.al.: Neuropsychiatric disorders caused by cobalamin deficiency in the absence of anemia or macrocytois. N Engl J Med 1988;318:1720-1728.
18)Vogiatzoglou, A. Determinants of Methylmalonic Acid in a Large Population: Implications for Assessment of Vitamin B12 Status. Clinical Chemistry (55)12: 2198-2206 (2009)