Medical Heresy: Low Cholesterol is Dangerous!

James Greenblatt, MD

Misleading Messages: What is the Truth about Cholesterol?
The cultural dogma is that cholesterol is an evil villain that needs to be eradicated for true health.  Given the unflagging efforts of the United States medical establishment over the last few decades to lower cholesterol and corresponding media saturation of food and drug promotions boasting cholesterol-lowering effects, it is understandable that most consumers are not concerned about having cholesterol levels that are too low.  Clinical practices appear to uphold the belief that “lower is better”, regardless of significant evidence to the contrary.  Opposing reports from aggressive cholesterol-lowering methods suggest that, for many patients, the potential cardiovascular benefits may come with unforeseen risks to mental health and behavior.  As a matter of fact, in 2012 the FDA was compelled to require black-box warnings on statins as a result of clinical trial outcomes indicating dangerous effects on cognition and psychological symptoms. Further research suggests that while statin drugs and other cholesterol-lowering agents have improved mortality rates for cardiovascular disease, total mortality has not experienced similar reductions, reflecting a rise in death by suicide or other consequence of mental disorders (Sahebzamani, 2013).  A prospective six-year cohort study of approximately 500 older adults provided startling data that individuals with lower serum total cholesterol (less than 6 mmol/L) had a higher risk of dying, independent of health or disease status (Tuikkala, 2010).

Cholesterol is a critical component of human biochemistry; indeed, it is so important that it is regularly synthesized by the liver and other organs throughout the body and is continuously recycled.  As a key structural constituent of cell membranes, cholesterol is essential for intracellular transport and communication, including signaling between neurons.  Synthesis of several hormones and Vitamin D also depend on cholesterol, providing additional clues to the connection between cholesterol and brain health.  In addition to other lipid molecules, cholesterol contributes to the approximately 60% dry weight of the brain composed of fat.  The brain relies heavily on lipids during growth and development and for optimal daily function, drawing on dietary and endogenous sources to fuel its extreme demands for energy.  The increased demand for cholesterol during adolescent brain development underlies the greater risk for psychopathology in teens and young adults.  Concurrent anatomical and neurotransmitter changes beginning in childhood persist until roughly age 21, a critical time when psychiatric disorders often erupt (Gogtay, 2004).

Clinical cholesterol panels measure blood lipid levels comprising triglycerides, low-density lipoprotein (LDL), high-density lipoproteins (HDL), and total cholesterol, which is a function of all three.  Normal values stretch from 125 to 200 mg/dl, and healthy levels vary by age, gender, race, health status, and family medical history.  Although recent media reports dismissed the contribution of high dietary cholesterol to serum status, the debate is far from over and the National Institutes of Health (NIH) continues to recommend dietary restriction of high-cholesterol foods (NIH, 2018).  Despite decades of clinical research and practice, experts still do not agree on “optimal” levels for LDL, HDL, or total cholesterol.  Medical treatment targets vary from lowering LDL, lowering total cholesterol, or raising HDL, leaving the public more confused than ever and creating a general fear of cholesterol.  And while consumers attempt to alter serum cholesterol through dietary and other lifestyle changes, data continue to accumulate showing the detrimental physical and psychological outcomes of fat avoidance. 

Like many health paradigms, a reductionist perspective on cholesterol as related only to cardiovascular health has neglected the extensive utility of these important molecules throughout the body.  Lipids including cholesterol play fundamental roles in human metabolism, and “healthy” levels can vary widely between individuals based on a complexity of factors.  David Horrobin, an ardent medical researcher who devoted much of his career to the relationship between lipids and mental health, developed a substantial hypothesis for the role of dietary fats in human anthropology.  He proposed that rapid advances in human evolution that enabled higher intellect and creativity occurred due to increases in fat storage in humans.  Focusing on schizophrenia, Horrobin suggested that the genetic factors influencing the severity of schizophrenia symptoms were the same markers that “made us human” (Horrobin, 1998).

Cholesterol’s Role in Mental Health
A significant connection between low cholesterol and poor psychiatric health has been emphasized through decades of observational and retrospective research studies.  Correlations with substance abuse, eating disorders, depression, and suicide strongly imply that cholesterol status influences mood and behavior.  Inadequate cholesterol levels may represent a shared etiological factor between these conditions and explain the overlapping continuum of pathology.  Low cholesterol reduces the function of serotonin, a neurotransmitter responsible for the regulation of emotion and decision-making.  Abnormal brain volumes, neural connectivity, and neurotransmitter function are present in patients with depression and eating disorders (Travis, 2015).  In Anorexia-Nervosa patients, low serum cholesterol significantly predicts depression, self-injury, and suicidal ideation (Favaro, 2004).  Research also suggests that anti-depressant medications may further lower serum cholesterol, counteracting any beneficial mechanisms (Sahebamani, 2003).  Lack of impulse control associated with drug addiction may also be attributed to poor cholesterol status.  An assessment of cocaine addicts following hospital discharge revealed that lower cholesterol values predicted relapse at each follow-up, suggesting that recovery requires an adequate supply of dietary lipids (Buydens, 2003).

Aggression can describe both physical and psychological behaviors directed towards the self or others, yet each of its manifestations has been linked to cholesterol status.  Violent conduct has been related to low cholesterol levels in patients ranging from adolescents with attention-deficit hyperactivity disorder (ADHD) to war veterans with post-traumatic stress disorder (PTSD) (Vilibic, 2014; Virkkunen, 1984).  While different genetic and biological mechanisms may be at play, cholesterol’s influence on hormones and neurotransmitters may provide at least one explanatory link (Hillbrand, 1999).  Imbalanced neurotransmitters inhibit the normal stress response, triggering expressions of fear at the root of aggressive actions.  A 3-month naturalistic observation of pre- and post-discharge psychiatric patients found significant associations between HDL cholesterol levels and violence, building upon more numerous data related to total cholesterol and highlighting HDL as a potential biomarker for risk of violence.  The authors reported strong evidence that insufficient cholesterol reduces the transportation capacity of serotonin in the central nervous system, interfering with the limbic brain’s affective and impulse responses (Eriksen, 2017). 

One of the most disturbing demonstrations of self-aggression is suicide.  A tragically growing public health issue, deaths by suicide are at their highest levels in three decades, increasing 24% between 1999 and 2014 to become the tenth leading cause of death in the United States (Curtin, 2016).  Attempts at self-harm and suicide are also rising in the adolescent population, with data suggesting a 65% increase in girls age 13 to 18 and reports of self-injury ranging from 15 to 30% of middle-, high-school, and college age students (Twenge, 2017).  Low cholesterol status again emerges as a common thread in otherwise healthy suicidal patients and those with depression and eating disorders, showing associations with abnormal brain volumes and Vitamin D concentrations (Grudet, 2014).  In spite of biomarker data obtained from clinical research, suicide prevention through biological strategies remains elusive. 

An Integrative Perspective on Cholesterol
Cholesterol levels should be monitored in all patients evaluated for depression, self-injury, and suicidal ideation.  With the number of prescriptions to anti-depressants and cholesterol-lowering drugs continuing to rise in patients young and old, it is imperative for clinicians to be aware of the undeniable influence of cholesterol status in both the etiology and treatment of mental health disorders.  Based on decades of clinical experience in my integrative psychiatry practice, genetic heritability and dietary cholesterol intake are highly predictive of mental health risk.  A family history of aggression, violence, or substance abuse may indicate a heritable metabolic defect affecting normal synthesis and recycling of serum cholesterol and suggesting a need for greater dietary intake.  Furthermore, a personal history of trauma, chronic stress, or eating disorders are flags for potential influences on cholesterol metabolism.

While consumption of high-cholesterol foods continues to be vilified in the battle against cardiovascular disease, inadequate dietary cholesterol is often overlooked.  Consensus on what represents low total serum cholesterol varies, but the normal range identified by the NIH suggests that levels above 125 mg/dL are adequate in most men and women (NIH, 2018).  While many clinicians recommend total cholesterol remain below 150 mg/dL, my concern is triggered in psychiatric patients with levels below 130 mg/dL, particularly in those with restrictive diets or with symptoms of irritability, lack of impulse control, or reckless behavior.  In these patients, gradually increasing total serum cholesterol over a period of three to six months has produced clear improvements in mood along with decreases in aggressive tendencies and any drug cravings.

The treatment protocol I have adopted in my integrative psychiatry practice for safely and effectively optimizing total cholesterol levels typically includes a recommendation to increase consumption of organic eggs, one of the richest sources of dietary cholesterol accompanied by protein, B-vitamins, choline, and other nutrients associated with brain health.  I also prescribe the use of digestive enzymes that contain lipase to enhance intestinal lipid digestion and absorption.  As a second-tier treatment strategy or for patients who avoid or are allergic to eggs, I recommend a supplemental form of cholesterol at a dose based on the individual’s cholesterol status.  New Beginnings Nutritionals’ Sonic Cholesterol delivers 250 mg of pure cholesterol per capsule, equivalent to the amount found in a single egg.  In addition to symptom monitoring, monthly cholesterol screening is necessary to adjust recommendations and prescriptions as blood levels improve.

It may be medical heresy to advocate for raising cholesterol, but only because of widespread ignorance and stubborn adherence to outdated information and methodology.  The World Health Organization predicts that by 2020, the global rate of suicide will increase to a death every 20 seconds, doubling the rate estimated in 2014.  This alarming societal epidemic highlighted by recent high-profile deaths and substantial data supporting the prevalence of low cholesterol among mental health patients provides an opportunity to expose a major, potentially preventable risk factor and a simple, straightforward treatment model that may save thousands of lives.  As knowledge of the link between diet and the brain grows, now is the time to reverse cholesterol’s erroneous reputation and recognize this essential nutrient as a critical component for mental health.

References:

1. Buydens-Branchey, L., & Branchey, M. (2003). Association between low plasma levels of cholesterol and relapse in cocaine addicts. Psychosomatic medicine, 65(1), 86-91.

2. Curtin, S. C., Warner, M., & Hedegaard, H. (2016). Increase in suicide in the United States, 1999-2014.

3. Eriksen, B. M. S., Bjørkly, S., Lockertsen, Ø., Færden, A., & Roaldset, J. O. (2017). Low cholesterol level as a risk marker of inpatient and post-discharge violence in acute psychiatry–A prospective study with a focus on gender differences. Psychiatry research, 255, 1-7.

4. Favaro, A., Caregaro, L., Di Pascoli, L., Brambilla, F., & Santonastaso, P. (2004). Total serum cholesterol and suicidality in anorexia nervosa. Psychosomatic Medicine, 66(4), 548-552.

5. Gogtay, N., Giedd, J. N., Lusk, L., Hayashi, K. M., Greenstein, D., Vaituzis, A. C., ... & Rapoport, J. L. (2004). Dynamic mapping of human cortical development during childhood through early adulthood. Proceedings of the National academy of Sciences of the United States of America, 101(21), 8174-8179.

6. Grudet, C., Malm, J., Westrin, Å., & Brundin, L. (2014). Suicidal patients are deficient in vitamin D, associated with a pro-inflammatory status in the blood. Psychoneuroendocrinology, 50, 210-219.

7. Hillbrand, M., & Spitz, R. T. (1999). Cholesterol and aggression. Aggression and violent behavior, 4(3), 359-370.

8. Horrobin, D. F. (1998). Schizophrenia: the illness that made us human. Medical hypotheses, 50(4), 269-288.

9. National Institutes of Health. (2018). Cholesterol Levels: What You Need to Know. Medline Plus Website. https://medlineplus.gov/cholesterollevelswhatyouneedtoknow.html#. Accessed 09 June 2018.

10. Sahebzamani, F. M., D'Aoust, R. F., Friedrich, D., Aiyer, A. N., Reis, S. E., & Kip, K. E. (2013). Relationship among low cholesterol levels, depressive symptoms, aggression, hostility, and cynicism. Journal of clinical lipidology, 7(3), 208-216.

11. Travis, K. E., Golden, N. H., Feldman, H. M., Solomon, M., Nguyen, J., Mezer, A., ... & Dougherty, R. F. (2015). Abnormal white matter properties in adolescent girls with anorexia nervosa. NeuroImage Clin. 9, 648–659.

12. Tuikkala, P., Hartikainen, S., Korhonen, M. J., Lavikainen, P., Kettunen, R., Sulkava, R., & Enlund, H. (2010). Serum total cholesterol levels and all-cause mortality in a home-dwelling elderly population: a six-year follow-up. Scandinavian journal of primary health care, 28(2), 121-127.

13. Twenge, J. M., Joiner, T. E., Rogers, M. L., & Martin, G. N. (2018). Increases in depressive symptoms, suicide-related outcomes, and suicide rates among US adolescents after 2010 and links to increased new media screen time. Clinical Psychological Science, 6(1), 3-17.

14. Vilibić, M., Jukić, V., Pandžić-Sakoman, M., Bilić, P., & Milošević, M. (2014). Association between total serum cholesterol and depression, aggression, and suicidal ideations in war veterans with posttraumatic stress disorder: a crosssectional study. Croatian medical journal, 55(5), 520-529.

15. Virkkunen, M., & Penttinen, H. (1984). Serum cholesterol in aggressive conduct disorder: a preliminary study. Biological Psychiatry.

Integrative Therapies for Obsessive Compulsive Disorder

James Greenblatt, MD

While it is human nature to occasionally ruminate or overanalyze important decisions, these thought patterns normally dissipate quickly freeing us of those fleeting moments of inner turmoil.  However, for those suffering from Obsessive Compulsive Disorder (OCD), letting go of repetitive thoughts is not so effortless.  Relentless ideas, impulses, or images inundate the brain leaving the individual mentally imprisoned to an existence of recurrent, irrational thought patterns.  These senseless obsessions often drive the individual to perform ritualistic behaviors or compulsions, in an effort to temporarily relieve their anxiety.  Sufferers stagger through life with a sense of pure powerlessness against their disorder; fully aware that the behavior is abnormal, yet unable to stop.

Psychotropic medications such as selective serotonin reuptake inhibitors (SSRI’s) and Anafranil and cognitive behavioral therapy are the conventional treatment options for Obsessive Compulsive Disorder. Sadly, the likelihood of complete recovery from OCD has not been shown to exceed 20% and relapse is quite common.  Inadequate treatment and limited biomedical options contribute to the high relapse rate as conventional medicine does not address underlying nutritional deficiencies or the root cause. Though unlikely to be caused by deficiencies alone, addressing vital nutrient depletions is a critical aspect of treating OCD since certain vitamins, minerals, and amino acids significantly impact serotonin neurotransmission.  Specifically, natural therapies including: 5-HTP, niacin (B3), pyridoxal-5-phosphate (B6), folate (5-MTHF), vitamin C, zinc, magnesium, inositol, and taurine are important to serotonin synthesis.  Therefore, the combination of aforementioned nutrients taken in therapeutic dosages should be part of integrative treatment approach for Obsessive Compulsive Disorder.

The fourth most common psychiatric illness in the United States, Obsessive Compulsive Disorder or “OCD” onset typically occurs by adolescence usually between the ages of 10-24, with one third of all cases appearing by age 15. In fact, OCD is said to be more common than asthma and diabetes (Schwartz, 1997). Despite its prevalence, it is often under diagnosed and under treated with more than half of those suffering receiving no treatment at all for their condition.  Gender does not affect susceptibility, as men and women are equally affected by this detrimental disorder. 

To fully grasp the inner workings of OCD, consider Jeffrey Schwartz’s description of “Brain Lock” (Schwartz, 1997) where four key structures of the brain become locked together sending false messages that the individual cannot interpret as false.  The brain is made up of two structures called the caudate nucleus and the putamen, which can be compared to a gearshift in a car.  According to Schwartz, “The caudate nucleus works like an automatic transmission for the front, or thinking part, of the brain…the putamen is the automatic transmission for the part of the brain that controls body movements… the caudate nucleus allows for the extremely efficient coordination of thought and movement during everyday activities.  In a person with OCD, however, the caudate nucleus is not shifting gears properly, and messages from the front part of the brain get stuck there.  In other words, the brain’s automatic transmission has a glitch.  The brain gets ‘stuck in gear’ and can’t shift to the next thought” (Schwartz, 1997).

It is clear that enhancing serotonin neurotransmission through psychotropic medications helps the brain “shift into gear” so to speak.   But what exactly causes this glitch that leads to serotonin deficiency syndrome? A number of factors including genes, diet, stress, neurotoxins, and inflammation are responsible for inadequate serotonin synthesis.  Amino acid availability for neurotransmitter synthesis is dependent upon certain digestive enzymes, and their activation is dependent on hydrochloric acid.  Without sufficient amino acid availability, neurotransmitter synthesis will suffer.  Specifically, availability of the essential amino acid L-tryptophan is required for serotonin production.  Because serotonin synthesis depends on the availability of L-tryptophan and essential cofactors including vitamin B3, folate (5-MTHF), vitamin B6, and zinc, serotonin levels will be less than optimal if any of the required building blocks are deficient.  The process of serotonin synthesis starts when L-tryptophan is converted into 5-hydroxytryptophan with the help of tryptophan hydroxylase (a vitamin B3 dependent enzyme), which requires 5-MTHF.  5-hydroxytryptophan (5-HTP) then converts to serotonin with the aid of decarboxylase, vitamin B6 dependent enzymes, and zinc.

Supplemental 5-hydoxytryptophan (5-HTP) can be beneficial for individuals as it essentially bypasses the need for L-tryptophan availability.  Easily crossing the blood brain barrier, 5-HTP works like a targeted missile directly increasing brain serotonin levels.  It does not require a transport molecule for crossing the blood brain barrier, and unlike L-tryptophan, it is shunted from incorporation into proteins and niacin conversion (Birdsall, 1998).  What’s more, promising research indicates that the therapeutic effect of 5-HTP compared to fluoxetine (Prozac), is actually equal (Jangid et al., 2013). Antidepressant effects are experienced in as little as two weeks with 5-HTP; effectively treating individuals with varying degrees of depression (Jangid et al., 2013).There has been four research studies looking at 5-HTP supplements specifically for OCD. Clinicians around the globe, for more than twenty years, have had success with amino precursors including 5-HTP for the treatment of OCD. I recommend starting all patients with 50 mg of 5-HTP and titrate slowly every 2 weeks up to a maximum of 200 mg per day. Side effects of 5-HTP include nausea, irritability, and possible anxiety.

In addition to the influence of digestive health on serotonin synthesis, absorption of vital minerals specifically zinc and magnesium, are also impacted by Hydrochloric Acid (HCL) availability.  Thus, if HCL and digestive enzyme production is low, mineral deficiencies will likely follow.  This is worth noting because optimal levels of zinc and magnesium are imperative to maintaining healthy serotonin levels, while moderating the activity of glutamate receptors. As stated previously, zinc is an important coenzyme required for decarboxylase activation and the conversion of 5-HTP to serotonin.  Magnesium also plays an essential role, aiding the conversion process of L-tryptophan to serotonin.

In addition to zinc and magnesium, folate plays a critical role in serotonin neurotransmission.  Specifically, the enzyme responsible for converting L-tryptophan to 5-HTP, requires 5-MTHF, also known as “L-Methylfolate.”  Without sufficient folate, L-tryptophan will struggle to convert to 5-HTP.  Research on depression and folate is extensive; hundreds of studies support the relationship between folate and depression.  Thus, it is imperative to consider folate status when treating OCD.   Specifically, low folate levels are associated with increased incidence of depression, poor response to antidepressants, and higher relapse rates.  Because dietary sources of folate are heat labile and easily oxidized (more than 50% is oxidized during food processing) folate malabsorption and deficiency is quite prevalent in our society.  To make matters worse, individuals taking certain medications such as anticonvulsants, oral contraceptives, antacids, antibiotics, and Metaformin are at increased risk of deficiency. 

Individuals that possess genetic polymorphisms in the gene coding for the methylenetetrahydrofolate reductase (MTHFR) gene are at high risk for low folate status due to reduced ability to convert folic acid to its active form. Folic acid requires a four step transformation process to be converted to L-methylfolate, where dietary folate requires three steps.  MTHFR polymorphisms reduce efficiency of this transformation process; severely impacting conversion of folic acid to L-methylfolate.  Since L-methylfolate is the active absorbable form of folate that crosses the blood brain barrier for use, inability to properly convert dietary or supplemental folic acid may cause folate deficiency (Lewis et al., 2006).

Inositol has proven particularly effective for SSRI resistant patients as well.  Specifically, OCD patients experiencing lack of response to SSRI’s or clomipramine have been examined.  There are research studies demonstrating dosages of 18/gms of inositol per day was effective in OCD treatment.  Improvement in symptoms had been reported at 6 weeks of treatment with no reported side effects (Fux et al., 1996).  A promising finding, inositol is an effective natural therapy for OCD treatment when taken on its own.  It is particularly helpful to individuals who are unresponsive to conventional SSRI treatment.  However, at this time use of inositol as an augmentation agent to improve SSRI function has not been proven effective (Fux et al., 1999).

Inositol’s effect on treatment resistant patients is likely due to its role in the neurotransmission process.  Operating as a secondary messenger, it enhances the sensitivity of serotonin receptors on the postsynaptic neuron using signal transduction.  Upon binding to its receptor, messages from serotonin are then translated into signals that are expressed through behaviors such as positive mood, relaxation, and reduced obsessions.  Due to its role in serotonin signaling, patients resistant to SSRI treatment may not necessarily have an issue with serotonin synthesis but rather decreased receptor sensitivity.

Controlled trials of inositol have confirmed therapeutic effects in a wide spectrum of psychiatric illnesses generally treated with SSRI’s including: OCD, Major Depressive Disorder, Panic Disorder, and Bulimia.  In particular, children exhibiting OCD symptoms have shown considerable life altering improvements with inositol treatment. For instance, “S.M.” a socially withdrawn, 11 year old child who obsessively feared fire and contamination, transformed into a “completely different child” with inositol treatment.  Similarly, “P.J.”, treated with inositol and 5-HTP, showed significant improvement in OCD symptoms.  A third clinical case, “C.K.” had suffered immensely with severe adverse side effects to Celexa and Prozac including aggressive thoughts of self-harm.  Upon treatment with inositol, no side effects were reported and minimal improvement was even displayed.  Even though research studies suggest 18 grams of Inositol per day, I start all patients with OCD on approximately 3 grams of Inositol per day (1/2 Tsp. 3 times per day).this minimizes GI side effects including bloating and nausea. If needed, Inositol dosages can be titrated up slowly with most patients responding below 12 grams per day.

Improving serotonin production and neurotransmission is integral to boosting serotonin levels and combating symptoms of OCD.  However, preventing over-activity of neurotransmitters should also be considered.  Taurine is an essential amino acid and precursor to GABA, an inhibitory neurotransmitter.  A regulatory agent, GABA helps maintain healthy serotonin levels and reuptake.  Widely known for its calming effect, taurine’s therapeutic use for anxiety and depression treatment has been explored.  In one study, animals fed a high taurine diet for 4 weeks exhibited anti-depressive behavior (Caletti, 2015).  Furthermore, a study on mice indicated a reduction in anxiety where taurine was administered 30 minutes before anxiety tests (Kong et al., 2006).  Though taurine does not directly target serotonin production, it is still worth noting as its inhibitory effect may reduce racing thoughts associated with anxiety disorders such as OCD.

Based on extensive scientific evidence supporting the relationship of aforementioned nutrients to serotonin production, as well as decades of clinical experience, I developed SeroPlus (https://www.nbnus.net/).   SeroPlus is a nutritional supplement to help patients with OCD and depression.   The formula provides serotonin building blocks including therapeutic doses of 5-HTP (direct precursor to serotonin), Inositol, and Taurine in addition to vital cofactors magnesium, vitamin C, pyridoxal-5- phosphate (activated B6), and Metafolin® (activated folate). Inositol elevates sensitization of serotonin receptors while taurine maintains healthy sympathetic nervous system tone and moderates serotonin activity and reuptake.  The formula also includes niacin and zinc picolinate which enhance availability of 5-HTP by reducing the amount of 5-HTP used for activation and absorption of these nutrients.  Synergistically, these ingredients work effectively together to optimize serotonin production and restore healthy serum levels of common deficiencies contributing to abnormalities in serotonin neurotransmission.

As with any psychiatric illness, treating OCD is complex and requires a comprehensive multi-prong approach beyond basic SSRI prescriptions and behavioral therapy.  Although directly enhancing serotonin production through natural therapies such as 5-HTP as well as correcting underlying B3, B6, zinc, magnesium, folate, and inositol deficiencies is at the heart of integrative treatment there are a number of alternative factors that may be contributing to the cause. Low levels of B12, DHA, and vitamin D must be addressed. 

A prisoner to their own thoughts, OCD sufferers are frustrated and searching for alternative treatment options.  The complex etiology of OCD includes genetics, inflammation, and the dysfunction of serotonin synthesis.  While SSRI’s may enhance serotonin synthesis, a number of OCD patients do not experience long term results.  Thus, identifying key nutrient depletions and replenishing them through dietary modification and supplementation is essential to increasing chances of long term recovery. 

James M. Greenblatt, MD, is the author of Finally Focused: The Breakthrough Natural Treatment Plan for ADHD (Harmony Books, 2017). He currently serves as Chief Medical Officer and Vice-President of Medical Services at Walden Behavioral Care, and he is an Assistant Clinical Professor of Psychiatry at Tufts University School of Medicine and Dartmouth Geisel School of Medicine. An acknowledged expert in integrative medicine, Dr. Greenblatt has lectured throughout the United States on the scientific evidence for nutritional interventions in psychiatry and mental illness. For more information, visit www.JamesGreenblattMD.com

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References

1. Birdsall. (1998). 5-Hydroxytryptophan: a clinically-effective serotonin precursor. Altern Med Rev. Aug; 3(4): 271-80.

2. Caletti. (2015). Antidepressant dose of taurine increases mRNA expression of GABAA receptor α2 subunit and BDNF in the hippocampus of diabetic rats. Behav Brain Res. 2015 Apr 15; 283:11-5.

3. Fux et al. (1996). Inositol treatment of obsessive-compulsive disorder. Am J Psychiatry, Vol 153(9) 1219-1221.

4. Fux et al. (1999). Inositol versus placebo augmentation of serotonin reuptake inhibitors in the treatment of obsessive-compulsive disorder: a double blind cross-over study. International Journal of Neuropsychopharmacology 2, 193-195.

5. Jangid et al. (2013) Comparative study of efficacy of l-5-hydroxytryptophan and fluoxetine in patients presenting with first depressive episode. Asian J Psychiatr. Feb;6(1):29-34

6. Kong. (2006). Effect of taurine on rat behaviors in three anxiety models. Pharmacol Biochem Behav. Feb; 83(2):271-6.

7. Milner. (1963). Ascorbic acid in chronic psychiatric patients. Brit J Psychiatr 109; 294-299.

8. Schwartz, Jeffrey M. Brain Lock: Free Yourself from Obsessive-Compulsive Behavior . Harper Perennial; 1st edition, 1997.

Integrative Treatments for Behavioral Problems in Children

By: James Greenblatt, MD

Attention deficit/hyperactivity disorder (ADHD) is a multifactorial condition that is influenced by genetic, biological, environmental, and nutritional factors. While there are numerous integrative therapies available including vitamins, minerals, herbs, neurofeedback, exercise, and meditation, individuals are unique and thus require personalized treatments based on their own biological needs identified through laboratory testing. In this article, we will discuss commonly overlooked mineral deficiencies and imbalances in the gastrointestinal flora that can exacerbate behavioral symptoms and impede the therapeutic effect of pharmacological treatment.

In the early 1960s, researchers discovered that zinc was an essential trace mineral necessary for normal growth and development. Zinc is also critical for immune function, and the activity of over 300 enzymes is dependent on zinc bioavailability. Zinc is a vital component of the central nervous system, maintaining neurotransmitter activity. This mineral enhances GABA, one of our main inhibitory/relaxation neurotransmitters. Moreover, zinc is needed as a co-factor to produce melatonin which helps regulate dopamine function.

Multiple studies have confirmed that not only are zinc levels lower in children with ADHD, but the extent of the deficiency is proportionately correlated with the severity of ADHD symptoms including inattention, hyperactivity, impulsivity, and conduct problems:

• Toren et al. (1996) found that almost one-third of 43 ADHD children aged 6-16 were severely deficient in serum zinc.

• Another study involving 48 ADHD children aged 5-10 demonstrated that most of the participants had serum zinc levels in the lowest 30% of the reference range.

• There is a highly significant inverse correlation between zinc level and parent and teacher ratings of inattention among children with ADHD (Arnold et al., 2005). A more recent study echoed the same findings, when researchers analyzed the zinc in the hair of 45 children with ADHD against 44 controls. They found that there was a relationship between hair zinc levels and worse overall ADHD symptoms (Shin et al., 2014).

• In a recent study, 70% of the 20 ADHD cases examined were zinc deficient. Those with lower hair zinc levels reported significantly increased symptoms of inattention, hyperactivity, and impulsivity (Elbaz et al., 2016).

• In a larger group of 118 children with ADHD, those with the lowest blood levels of zinc had the most severe conduct problems, anxiety, and hyperactivity as rated by their parents (Oner et al., 2010).

In children with ADHD, plasma zinc levels were shown to directly affect information processing via event related potentials which reflect brain activity. In ADHD children compared to controls, the amplitudes of P3 waves in frontal and parietal brain regions were significantly lower (worse working memory) and the latency of P3 in the parietal region was significantly longer (slower information processing). Unsurprisingly, plasma zinc levels were significantly lower in the ADHD children compared to the control children. When a low-zinc ADHD subgroup was compared to a nondeficient ADHD subgroup, the latencies of N2 in frontal and parietal brain regions were significantly shorter (worse information processing and inhibition) (Yorbik et al., 2008).

Supplementation with zinc is more effective at improving ADHD symptoms when compared to placebo, and can also be an effective adjuvant therapy to enhance the therapeutic effect of stimulant medication without increasing the dosage. When 400 ADHD children aged 6-14 were randomized to zinc sulfate 150 mg/day or placebo for 12 weeks, those taking zinc had significantly reduced symptoms of hyperactivity, impulsivity, and impaired socialization (Bilici et al., 2004). Similarly, when over 200 children were randomized to zinc 15 mg/day or to placebo for 10 weeks, those taking zinc saw significant improvement in attention, hyperactivity, oppositional behavior, and conduct disorder. And these children had normal zinc levels to begin with (Üçkardeş et al., 2009). In a small study of 18 boys with ADHD, higher baseline hair zinc levels predicted better behavioral response to amphetamine (Arnold et al., 1990). In a six-week double blind, placebo controlled trial, researchers assessed the effects of zinc in combination with methylphenidate (Ritalin). 44 children aged 5-11 were randomized to methylphenidate plus zinc sulfate 55 mg/day or methylphenidate plus placebo. At week 6, those taking zinc had significantly better scores on the Parent and Teacher ADHD Rating Scale (Akhondzadeh et al., 200452 children aged 6-14 with ADHD were randomized to zinc glycinate 15 mg/day or placebo for 13 weeks. For the first 8 weeks, they only took zinc then for the last 5 weeks they also took d-amphetamine. The optimal absolute mg/day amphetamine dose with zinc was 43% lower than with placebo (Arnold et al., 2011).

Copper is an essential trace mineral that plays an active role in the synthesis of dopamine and norepinephrine. However, excess copper can manifest as displays of aggression, hyperactivity, insomnia, and anxiety. Elevated copper levels can also cause low zinc levels and reduce the efficacy of medications commonly used to treat ADHD.

Copper may affect ADHD through its role in antioxidant status. Copper/Zinc superoxide dismutase (SOD-1) is a key enzyme in our antioxidant defense system. Both copper and zinc participate in SOD enzymatic activities that protect against free radical damage. In a study on 22 ADHD children and 20 controls, serum Copper/Zinc SOD levels of ADHD children were significantly lower in individuals with high serum copper when compared to controls. It is also hypothesized that excess copper can damage dopamine brain cells by destroying antioxidant defenses, such as lowering Copper/Zinc SOD levels (Russo, 2010).

In a randomized controlled trial on 80 adults with ADHD, lower baseline copper levels were associated with better response to treatment with a vitamin-mineral supplement (Rucklidge et al., 2014). Unfortunately, even copper levels that are considered normal can negatively affect cognition. In a group of 600 adolescents with normal copper levels, blood copper was associated with decreased sustained attention and short-term memory (Kicinski et al., 2015).

Magnesium is part of 300 enzymes that utilize ATP (cellular energy) and is important for nerve transmission. It is involved in the function of the serotonin, noradrenaline, and dopamine receptors. Magnesium has been progressively declining in our food supply due to increased consumption of processed foods. The use of medications, presence of stress, and caffeine and soft drink consumption also deplete magnesium, and it is estimated that 50% of Americans are deficient in magnesium (Mosfegh et al., 2009).

Symptoms of magnesium deficiency include irritability, difficulty with concentration, insomnia, depression, and anxiety. A prospective population-based cohort of over 600 adolescents at the 14- and 17-year follow-ups found that higher dietary intake of magnesium was significantly associated with reduced externalizing behaviors (attention problems, aggressiveness, delinquency) (Black et al., 2015). Because up to 95% of those with ADHD are deficient in magnesium, almost all ADHD children can benefit from magnesium supplementation (Kozielec & Starobrat-Hermelin, 1997).

In a recent study on 25 patients with ADHD aged 6-16, 72% of children were deficient in magnesium and there was a significant correlation between hair magnesium, total IQ, and hyperactivity. The magnesium deficient children were randomized to magnesium supplementation 200 mg/day plus standard medical treatment or to standard medical therapy alone for 8 weeks. Those taking magnesium saw a significant improvement in hyperactivity, impulsivity, inattention, opposition, and conceptual level while those taking medication alone did not see these improvements (El Baza et al., 2015).

Supplements of magnesium plus vitamin B6, which increases magnesium absorption, have shown promise for reducing ADHD symptoms. One study on 52 children with ADHD found that 58% had low red blood cell magnesium levels. All the children were given preparations of magnesium plus vitamin B6 100 mg/day for a period of 1 to 6 months. In all patients, physical aggression, instability, attention at school, muscle rigidity, spasms, and twitching were improved. One of the treated children was a six-year old identified as “J”. Initially, J suffered from aggressiveness, anxiety, inattention, and lack of self-control. After taking magnesium supplements, he reported better sleep and concentration and no methylphenidate was needed (Mousain-Bosc et al., 2004). A later study by the same researchers also found that 40 children with ADHD had significantly lower red blood cell magnesium values than control children. Likewise, a magnesium-vitamin B6 regimen for at least 2 months significantly improved hyperactivity, aggressiveness, and school attention. The researchers concluded, “As chronic magnesium deficiency was shown to be associated to hyperactivity, irritability, sleep disturbances, and poor attention at school, magnesium supplementation as well as other traditional therapeutic treatments, could be required in children with ADHD” (Mousain-Bosc et al., 2006). In a larger study of 122 children with ADHD aged 6-11, 30 days of magnesium-vitamin B6 supplementation led to improved anxiety, attention, and hyperactivity. On a battery of tests, magnesium treatment increased attention, work productivity, task performance, and decreased the proportion of errors. The EEG of treated children showed positive changes as well, with brain waves significantly normalizing (Nogovitsina & Levitina, 2007).

There has also been a considerable amount of research illustrating the symbiotic, bidirectional relationship between the brain and the gut, and animal studies have demonstrated how certain strains of bacteria, or lack thereof, can alter cognitive and emotional processes. In the presence of dysbiosis, where “bad” bacteria outnumber the “good,” harmful strains of bacteria can proliferate and cause behavioral disturbances.

HPHPA is a harmful byproduct of some strains of the bacterium Clostridium that can disrupt the normal gut environment. Elevated urinary levels are commonly seen in ADHD children, especially those with poor response to stimulants. HPHPA inhibits the conversion of dopamine to norepinephrine. This causes dopamine to accumulate, resulting in decreased attention and focus. A patient should especially be tested for HPHPA if he or she experiences stimulant side effects such as irritability, agitation, or anxiety. ADHD medications work by increasing dopamine. But high HPHPA levels prevent the breakdown of dopamine, exacerbating symptoms. HPHPA must be cleared before medications will be helpful. Probiotics, good bacteria found in fermented food such as yogurt, or antibiotics can be used to lower HPHPA.

Intestinal overgrowth of Candida yeast is seen in some children with ADHD, mostly in those with a diet high in sugar that feed Candida, or in those who have received many rounds of antibiotics for recurrent ear infections. Antibiotics are effective at resolving infections by eradicating all bacteria, including the good bacteria. An early study found that children with the greatest history of ear infections (and presumably the greatest frequency of antibiotic use) had an increased chance for developing hyperactivity later (Hagerman & Falkenstein, 1987). Toxins produced by Candida can enter the bloodstream and then enter the brain where they can cause changes leading to hyperactivity and poor attention span. Fortunately, the presence of HPHPA and other yeast overgrowth can be easily detected with an organic acids test or with a stool sample. Candida can be treated with probiotics, antifungal foods (e.g. garlic, oregano, ginger), and a lower sugar diet. In some cases, a regimen of antibiotics and probiotics can be useful in reestablishing a healthy gut flora.

Nutritional augmentation strategies are frequently used as part of the integrative clinician’s toolbox to treat behavioral disorders in children. It is important for healthcare providers to collaborate and communicate with caregivers of children with behavioral disorders to discern whether other complementary therapies could be incorporated into treatment. By carefully assessing a patient’s whole health history and conducting appropriate laboratory testing, providers can make informed treatment recommendations that is tailored specifically for the individual.

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References

Akhondzadeh, et al (2004). Zinc sulfate as an adjunct to methylphenidate for the treatment of attention deficit hyperactivity disorder in children: A double blind and randomized trial ISRCTN64132371. BMC Psychiatry, 4, 9.

Arnold et al. (1990). Does hair zinc predict amphetamine improvement of ADD/hyperactivity? The International Journal of Neuroscience, 50(1-2), 103-7.

Arnold et al. (2005). Serum zinc correlates with parent- and teacher- rated inattention in children with attention-deficit/hyperactivity disorder. Journal of Child and Adolescent Psychopharmacology, 15(4), 628-36.

Arnold et al. (2011). Zinc for attention-deficit/hyperactivity disorder: Placebo-controlled double-blind pilot trial alone and combined with amphetamine. Journal of Child and Adolescent Psychopharmacology, 21(1), 1-19.

Bilici et al. (2004). Double-blind, placebo-controlled study of zinc sulfate in the treatment of attention deficit hyperactivity disorder. Progress in Neuropsychopharmacology & Biological Psychiatry, 28(1), 181-190.

Black et al. (2015). Low dietary intake of magnesium is associated with increased externalising behaviours in adolescents. Public Health Nutrition, 18(10), 1824-30.

Elbaz et al. (2016). Magnesium, zinc and copper estimation in children with attention deficit hyperactivity disorder (ADHD). Egyptian Journal of Medical Human Genetics, Egyptian Journal of Medical Human Genetics, in press.

El Baza et al. (2016). Magnesium supplementation in children with attention deficit hyperactivity disorder. Egyptian Journal of Medical Human Genetics, 17(1), 63-70.

Hagerman & Falkenstein. (1987). An Association Between Recurrent Otitis Media in Infancy and Later Hyperactivity. Clinical Pediatrics, 26(5), 253.

Kicinski et al. (2015). Neurobehavioral function and low-level metal exposure in adolescents. International Journal of Hygiene and Environmental Health, 218(1), 139-146.

Kozielec & Starobrat-Hermelin. (1997). Assessment of magnesium levels in children with attention deficit hyperactivity disorder (ADHD). Magnesium Research: Official Organ Of The International Society For The Development Of Research On Magnesium, 10(2), 143-148.

Moshfegh et al. (2009). What We Eat in America, NHANES 2005–2006: Usual Nutrient Intakes from Food and Water Compared to 1997 Dietary Reference Intakes for Vitamin D, Calcium, Phosphorus, and Magnesium. U.S. Department of Agriculture, Agricultural Research Service: Washington, DC, USA.

Mousain-Bosc et al. (2004). Magnesium VitB6 intake reduces central nervous system hyperexcitability in children. Journal Of The American College Of Nutrition, 23(5), 545S-548S.

Mousain-Bosc et al. (2006). Improvement of neurobehavioral disorders in children supplemented with magnesium-vitamin B6. I. Attention deficit hyperactivity disorders. Magnesium Research: Official Organ Of The International Society For The Development Of Research On Magnesium, 19(1), 46-52.

Nogovitsina & Levitina. (2007). Neurological aspects of the clinical features, pathophysiology, and corrections of impairments in attention deficit hyperactivity disorder. Neuroscience and Behavioral Physiology, 37(3), 199-202.

Oner et al. (2010). Effects of Zinc and Ferritin Levels on Parent and Teacher Reported Symptom Scores in Attention Deficit Hyperactivity Disorder. Child Psychiatry and Human Development, 41(4), 441-447.

Rucklidge et al. (2014). Moderators of treatment response in adults with ADHD treated with a vitamin–mineral supplement. Progress in Neuropsychopharmacology & Biological Psychiatry, 50, 163-171.

Russo, A. (2010). Decreased Serum Cu/Zn SOD Associated with High Copper in Children with Attention Deficit Hyperactivity Disorder (ADHD). Journal of Central Nervous System Disease, 2, 9-14.

Shin et al. (2014). The Relationship between Hair Zinc and Lead Levels and Clinical Features of Attention-Deficit Hyperactivity Disorder. Journal of the Korean Academy of Child and Adolescent Psychiatry, 25(1), 28-36.

Toren et al. (1996). Zinc deficiency in attention-deficit hyperactivity disorder. Biological Psychiatry, 40(12), 1308-1310.

Üçkardeş et al. (2009). Effects of zinc supplementation on parent and teacher behaviour rating scores in low socioeconomic level Turkish primary school children. Acta Paediatrica, 98(4), 731-736.

Yorbik et al. (2008). Potential effects of zinc on information processing in boys with attention deficit hyperactivity disorder. Progress in Neuropsychopharmacology & Biological Psychiatry, 32(3), 662-667.

The Effect of Vitamin D on Psychosis and Schizophrenia

JAMES GREENBLATT, MD

Vitamin D deficiency has been linked to a wide range of major psychiatric illnesses and is an emerging area of interest for researchers. From my experience working with individuals with psychosis and schizophrenia in both inpatient and outpatient settings, I have often found low vitamin D levels in this patient population where the severity of symptoms were inversely correlated to serum vitamin D levels. Most recently, laboratory tests of individuals with schizophrenia, psychosis, elective mutism, and bipolar disorders revealed consistent serum vitamin D levels below 20 ng/ml. As vitamin D levels normalized, symptoms improved. While the mechanism is unclear, recent research suggests that vitamin D’s action on the regulation of inflammatory and immunological processes likely affects the manifestation of clinical symptoms and treatment response in schizophrenic patients (Chiang, Natarajan, & Fan, 2016).

The link between vitamin D deficiency and the development of schizophrenia has been researched among patients of all ages around the globe. One meta-analysis reviewed 19 studies published between 1988 and 2013 and found a strong association between vitamin D deficiency and schizophrenia. Of the 2,804 participants from these studies, over 65% of the participants with schizophrenia were vitamin D deficient. Vitamin D deficient participants were 2.16 times more likely to have schizophrenia than vitamin D sufficient participants (Valipour, Saneei, & Esmaillzadeh, 2014).

The risk of schizophrenia and vitamin D status vary with season of birth, latitude, and skin pigmentation. The UV rays required to make vitamin D are reduced in the months most associated with an increase in the birth of individuals who later develop schizophrenia. One review including a total of 437,710 individuals with schizophrenia found that most individuals were born in January and February. These newborns were thus exposed to lower levels of UV rays in their prenatal and perinatal periods. An increased rate of schizophrenia is also seen at higher latitudes, especially among immigrants. This may again be related to UV availability and subsequent vitamin D status. At higher latitudes, a dark skinned individual will also have a more pronounced reduction in vitamin D than a lighter skinned individual. The lighter skinned individual will have less melanin which allows the skin to absorb UV rays more effectively. It is estimated that individuals with darker skin at higher latitudes are more likely to develop schizophrenia than the general population (Chiang et al., 2016).

Swedish researchers reviewed medical charts at a psychiatric outpatient department to identify possible predictors of vitamin D deficiency. Over 85% of the 117 psychiatric patients had suboptimal vitamin D levels. Those with schizophrenia and autism had the lowest levels. Middle East, Mediterranean, South-East Asian or African ethnic origin were strong predictors of low vitamin D. The patients receiving vitamin D supplements to correct their deficiencies achieved considerable improvement of psychosis and depression symptoms (Humble et al., 2010).

Vitamin D concentrations were measured in 50 schizophrenia patients in Israel aged 19-65. Lower mean vitamin D concentrations were detected among patients with schizophrenia (15 ng/ml) compared to controls (20 ng/ml) after adjusting for the impact of sun exposure and supplements (Itzhaky et al., 2012). Likewise, 92% of 102 adult psychiatric inpatients in New Zealand also had suboptimal vitamin D levels and were more than twice as likely as Europeans to have severely deficient levels below <10 ng/ml (Menkes et al., 2012).

In a prospective birth cohort of 3,182 children in England, researchers measured vitamin D levels at age 9.8 years and assessed psychotic experiences at age 12.8 years. Vitamin D concentrations during childhood were associated with psychotic experiences during early adolescence. If psychotic experiences are related to the development of schizophrenia, this supports a possible protective association of higher vitamin D concentrations with schizophrenia (Tolppanen et al., 2012).

Vitamin D deficiency is associated with more severe symptoms. Cross sectional analyses were carried out on mentally ill adolescents aged 12-18 who required either inpatient or partial hospitalization. Of the 104 patients evaluated, 72% had insufficient vitamin D levels. Vitamin D status was related to mental illness severity. Those with vitamin D deficiency were 3.5 times more likely to have hallucinations, paranoia, or delusions (Gracious et al., 2012). A second study supports this finding. Vitamin D was analyzed from 20 patients with first-episode schizophrenia. Greater severity of negative symptoms (blunted affect, emotional withdrawal, poor rapport, passive-apathetic social withdrawal, abstract thinking, and stereotyped thinking) was strongly correlated with lower vitamin D status. Lower vitamin D levels were also associated with more severe overall cognitive deficits (Graham et al., 2015).

McGrath et al. (2010) investigated the relationship between neonatal vitamin D status and later risk of schizophrenia. They identified 424 cases with schizophrenia from the Danish Psychiatric Central Register and analyzed their neonatal dried blood spots. Not surprisingly they found a significant seasonal variation in vitamin D status and significantly lower levels of vitamin D in the offspring of mothers who immigrated to Denmark. They also found that those with lower neonatal concentrations of vitamin D had an increased risk of schizophrenia. The researchers estimated that if all these neonates had optimal vitamin D levels, over 40% of schizophrenia cases could have been averted.

The same group of researchers also discovered that taking vitamin D supplements during the first year of life is associated with a reduced risk of schizophrenia in males. They looked at a Finnish birth cohort and collected data about the frequency and dose of vitamin D supplementation during infancy. Males who regularly took vitamin D supplements had an 88% decreased risk of schizophrenia compared to those who never took supplements (McGrath et al., 2004).

The mechanism underlying this nutrient-illness relationship can only be speculated upon. Those with schizophrenia commonly have elevated markers of inflammation. Cells that are low in vitamin D produce high levels of inflammatory cytokines while cells with adequate vitamin D release significantly less of these cytokines. Thus there may be an anti-inflammatory mechanism (Chiang et al., 2016). Vitamin D regulates the transcription of many genes involved in pathways implicated in schizophrenia, including genes involved in synaptic plasticity, neuronal development, and protection against oxidative stress (Graham et al., 2015). Animal studies show that vitamin D deficiency in the gestational period affects dopamine metabolism and alters the dopamine system in the developing brain. Dopamine has been implicated in the pathogenesis of schizophrenia. Vitamin D deficiency during the gestational period can also affect brain structures that are associated with schizophrenia (Valipour, Saneei, & Esmaillzadeh, 2014).

While there is a lack of trials analyzing vitamin D supplements in the treatment of psychosis and schizophrenia, individuals with low levels of vitamin D within this patient population will tend to benefit from supplementation. Based on over 25 years of clinical experience, I have observed significant improvement in treatment outcomes utilizing vitamin D 5,000 to 10,000 i.u. once daily as an adjunct therapy. Serum vitamin D levels should be re-evaluated every two months until optimal levels are achieved.

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REFERENCES

1. Chiang, M., Natarajan, R., & Xiaoduo, F. (2016). Vitamin D in schizophrenia: a clinical review. Evidence Based Mental Health, 19(1), 6-9.

2. Cieslak, K., Feingold, J., Antonius, D., Walsh-Messinger, J., Dracxler, R., Rosedale, M., & ... Malaspina, D. (2014). Low vitamin D levels predict clinical features of schizophrenia.

3. Crews, M., Lally, J., Gardner-Sood, P., Howes, O., Bonaccorso, S., Smith, S., & ... Gaughran, F. (2013). Vitamin D deficiency in first episode psychosis: A case–control study. Schizophrenia Research, 150(Special Section: Negative Symptoms), 533-537.

4. Graham, K., Lieberman, J. , Lansing, K., Perkins, D., Calikoglu, A., & Keefe, R. (2015). Relationship of low vitamin D status with positive, negative and cognitive symptom domains in people with first-episode schizophrenia. Early Intervention In Psychiatry, 9(5), 397-405. Schizophrenia Research, 159(2/3), 543-545.

5. Hedelin, M., Löf, M., Olsson, M., Lewander, T., Nilsson, B., Hultman, C. M., & Weiderpass, E. (2010). Dietary intake of fish, omega-3, omega-6 polyunsaturated fatty acids and vitamin D and the prevalence of psychotic-like symptoms in a cohort of 33,000 women from the general population. BMC Psychiatry, 10,38.

6. Humble, M. B., Gustafsson, S., & Bejerot, S. (2010). Low serum levels of 25-hydroxyvitamin D (25-OHD) among psychiatric out-patients in Sweden: Relations with season, age, ethnic origin and psychiatric diagnosis. Journal Of Steroid Biochemistry And Molecular Biology, 121(Proceedings of the 14th Vitamin D Workshop), 467-470.

7. Itzhaky, D., Bogomolni, A., Amital, D., Arnson, Y., Amital, H., & Gorden, K. (2012). Low serum Vitamin D concentrations in patients with schizophrenia. Israel Medical Association Journal, 14(2), 88-92.

8. McGrath, J., Saari, K., Hakko, H., Jokelainen, J., Jones, P., Järvelin, M., & ... Isohanni, M. (2004). Vitamin D supplementation during the first year of life and risk of schizophrenia: a Finnish birth cohort study. Schizophrenia Research, 67, 237-245.

9. McGrath, J. J., Eyles, D. W., Pedersen, C. B., Anderson, C., Ko, P., Burne, T. H., & ... Mortensen, P. B. (2010). Neonatal Vitamin D status and risk of schizophrenia: a population-based case-control study. Archives Of General Psychiatry, (9), 889.

10. Menkes, D., Marsh, R., Lancaster, K., Grant, M., Dean, P., & du Toit, S. (2012). Vitamin D status of psychiatric inpatients in New Zealand's Waikato region. BMC Psychiatry, 12, 68.

11. Shivakumar, V., Kalmady, S. V., Amaresha, A. C., Jose, D., Narayanaswamy, J. C., Agarwal, S. M., & ... Gangadhar, B. N. (2015). Serum vitamin D and hippocampal gray matter volume in schizophrenia. Psychiatry Research, 233(2), 175-179.

12. Tolppanen, A., Sayers, A., Fraser, W. D., Lewis, G., Zammit, S., McGrath, J., & Lawlor, D. A. (2012). Serum 25-Hydroxyvitamin D3 and D2 and Non-Clinical Psychotic Experiences in Childhood. Plos ONE, 7(7), 1-8.

13. Valipour, G., Saneei, P., & Esmaillzadeh, A. (2014). Serum vitamin D levels in relation to schizophrenia: a systematic review and meta-analysis of observational studies. The Journal Of Clinical Endocrinology And Metabolism, 99(10), 3863-3872.

14. Yüksel, R. N., Altunsoy, N., Tikir, B., Cingi Külük, M., Unal, K., Goka, S., … Goka, E. (2014). Correlation between total vitamin D levels and psychotic psychopathology in patients with schizophrenia: therapeutic implications for add-on vitamin D augmentation. Therapeutic Advances in Psychopharmacology, 4(6), 268–275.

Urine Calcium and Magnesium in Adults: Recommended Test for Nutritional Adequacy

William Shaw, PhD

Calcium
Calcium is one of the most tightly regulated substances in the body. In addition to the role of calcium as a structural element in bones and teeth (99% of the body’s calcium is in the bones), calcium is critically needed for nerve function. When calcium in the plasma drops about 30%, the person may develop tetany, a condition that is often fatal due to overstimulation of the nerves in both the central nervous system and peripheral nervous system, leading to tetanic contraction of the skeletal muscles. The concentration of calcium in the plasma is one of the most constant laboratory values ever measured. In the great majority of normal people, calcium only varies from 9-11 mg per dL, regardless of the diet (1). The reason is a complex hormonal system that utilizes the bones as a source of calcium. This regulatory system employs the parathyroid gland that secretes parathyroid hormone or parathormone to digest the bones and release calcium when there is only a small decrease in the plasma calcium. Parathormone also increases the absorption of calcium from the gastrointestinal tract and the kidney tubules. When calcium rises in the plasma, parathormone secretion decreases, depositing more calcium in the bones while renal and gastrointestinal absorption are decreased.  Calcitonin, a polypeptide hormone produced by the thyroid gland, opposes the effects of parathyroid hormone. In addition, vitamin D increases the absorption of calcium from the gastrointestinal tracts and the kidney tubules like parathyroid hormone but has little effect on digesting bones to release calcium. One of the most controversial and misunderstood topics is what is the optimum nutritional intake of calcium and vitamin D. In the center of the controversy is the role of calcium in the initiation of plaque in the arteries, leading to atherosclerosis and cardiovascular disease. 

An average adult ingests about 750 mg per day of calcium and secretes about 625 mg of calcium in the intestinal juices. If all the ingested calcium is absorbed, there would be a net absorption of 125 mg per day of calcium. Since the average person excretes about 125 mg calcium per day in the urine, the average person has a zero net calcium balance except when bone is being deposited. If bone is being deposited due to the stress of exercise or following a fracture, the regulation of the amount of urinary calcium excretion is the major factor to allow for bone growth. One of the major factors that prevents calcium absorption is the presence of high amounts of oxalates in the diet. The human body has the ability to make some oxalate endogenously, perhaps about 40 mg per day in individuals with a favorable genetic makeup. A low oxalate diet contains less than 50 mg per day of oxalates while a high oxalate diet with two cups or more of spinach, nuts, and berries in a smoothie or salad per day could easily contain 1500 mg per day of oxalates. Such high amounts of oxalates readily use up the 125 mg of available calcium, forming insoluble calcium oxalate salts which can deposit in every organ of the body. These deposits can easily initiate endothelial damage that can lead to strokes and myocardial infarctions (heart attacks) and such oxalate deposits have been detected in atherosclerotic lesions. The person on a high oxalate diet will have a much greater need for calcium and/or magnesium than the person on a low oxalate diet.       

Since urine is the major controlling element for maintaining calcium balance that is under tight hormonal control, it appears to me that urine calcium is the best indicator of adequate dietary calcium. The most common reasons for low urine calcium are inadequate dietary calcium and/or a high oxalate diet.  Other reasons for calcium deficiency include hypoparathyroidism, pseudohypoparathyroidism, vitamin D deficiency, nephrosis, nephritis, bone cancer, hypothyroidism, celiac disease, and malabsorption disorders.

The most common reason for high urine calcium is a diet high in calcium. Other reasons for calcium excess are vitamin D intoxication, hyperparathyroidism, osteolytic bone metastases, myeloma, excessive immobilization, Cushing’s syndrome, acromegaly, distal renal tubular acidosis, thyrotoxicosis, Paget’s disease, Fanconi’s syndrome, schistosomiasis, breast and bladder cancers, and sarcoidosis.

Magnesium
Magnesium is an essential element like calcium and is also in the bones (66% of the body’s magnesium is in the bones). It is a cofactor with many enzymatic reactions especially those requiring vitamin B6. Like extremely low calcium, extremely low magnesium can also cause tetany of the muscles.

Low magnesium
The most common reason for low urine magnesium is low magnesium in the diet. Low magnesium in the diet may increase the incidence of oxalate crystal formation in the tissues and kidney stones. Less common causes of low magnesium include celiac disease, other malabsorption disorders, dysbiosis, vitamin D deficiency, pancreatic insufficiency, and hypothyroidism. Early signs of magnesium deficiency include loss of appetite, nausea, vomiting, migraine headaches, fatigue, and weakness. As magnesium deficiency worsens, numbness, tingling, muscle contractions and cramps, seizures, personality changes, anxiety, depression, attention deficit, abnormal heart rhythms, and coronary spasms can occur. Low urinary magnesium for long time periods is associated with increased risk of ischemic heart disease.

High magnesium
The most common reason for high urine magnesium is high magnesium in the diet. Less common causes of high urine magnesium include alcoholism, diuretic use, primary aldosteronism, hyperthyroidism, vitamin D excess, gentamicin toxicity, and cis-platinum toxicity.  Increased urinary magnesium excretion can occur in people with insulin resistance and/or type 2 diabetes. Symptoms of marked magnesium excess can include diarrhea, hypotension, nausea, vomiting, facial flushing, retention of urine, ileus, depression, lethargy before progressing to muscle weakness, difficulty breathing, extreme hypotension, irregular heartbeat, and cardiac arrest.

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REFERENECS

1. Guyton, Arthur. Textbook of Medical Physiology,3rd edition. WB Saunders Co, Philadelphia, 1966,pgs1100-1118.

2. Fleming, CR, et al. The importance of urinary magnesium values in patients with gut failure. Mayo Clinic Proceedings. 1996 Jan;71(1):21-4.

Rickets and dangerous eye-poking behavior in autism associated with calcium deficiency: Preventing and detecting deficiency with a simple urine test for calcium and magnesium

William Shaw, PhD

Failure to provide adequate calcium to persons on the autistic spectrum is very dangerous and could lead to the loss of the eyes due to severe eye-poking behavior. This is an especially important topic because some individuals like Amy Yasko warns that calcium may cause overstimulation of neurons. Every element in our food and drink including water may cause death with excess intake but you will not find skull and cross-bone warnings on bottled water at the supermarket. The most relevant question is: How much calcium in the diet and in supplements is excessive?

 Calcium deficiency can be a severe problem in normal children on a milk-free and dairy-free diet since milk is a significant source of protein, vitamin D, and calcium needed for strong bones and teeth. Some physicians have reported that rickets (1), a severe bone deformity, occurred in children with autism on the gluten and casein-free diet who did not receive added calcium supplements. Calcium and vitamin D supplementation is essential to children on a casein-free diet since most children with autism do not eat substantial amounts of other calcium-rich foods. Failure to provide adequate calcium to children on casein-free diets leads physicians to view such parents as negligent and ignorant and leads to skepticism about other nonstandard treatments for autism.

Children with autism may have an even more severe problem with calcium deficiency. Mary Coleman, M.D. (2) reported that children with autism who are calcium deficient are much more likely to poke out their eyes and a substantial number of children with autism have done so. I have talked to numerous parents of children with autism that began to touch their eyes after starting the casein-free diet. This abnormal behavior is associated with low urine calcium; blood calcium levels were usually normal. Parathyroid hormone, calcitonin, and vitamin D were all normal in patients with autism but all of them had low urine calcium. Treatment with calcium supplementation prevents this behavior but dietary supplementation with high calcium foods does not. (I suspect that this behavior is due to increased eye pain due to high deposits of oxalate crystals in the eye. Oxalates are high in urine samples of children with autism and can deposit in many tissues including the eyes.  Low calcium may act to intensify this pain and poking out the eye relieves the pain.) Dr. Coleman also found that speech developed very quickly after calcium supplementation in a portion of mute children with autism who had low urine calcium. In one case, according to a parent who contacted me, her child with autism persisted in poking at the eyes even after one eye had been partially poked out and surgically re-implanted. Calcium supplementation stopped this behavior immediately. I am aware of many other children with eye-poking behavior in which calcium supplements stopped this behavior in less than two days. Verbal autistic children say that their eye pain is severe and that calcium supplementation stopped their pain quickly. In Coleman’s study of 78 children with autism, 20% had urine calcium values two standard deviations below the normal child’s range for urine calcium. Clearly, this extremely low group requires supplementation with calcium. I would recommend calcium supplementation for any child below the mean value urine calcium for normal children of the same age.

Magnesium research in autism is often combined with research on vitamin B6 since the two nutritional factors work together in a host of biochemical reactions. In one study in France (4), children on the autistic spectrum were given 6 mg per kilogram of body weight per day of magnesium and 0.6 mg per kilogram body weight of vitamin B6. This supplementation improved autistic symptoms including the following: social interactions (23/33), communication (24/33), stereotyped restricted behavior (18/33), and abnormal/delayed functioning (17/33). When the Mg-B6 treatment was stopped, autistic symptoms reappeared in a few weeks. Low magnesium levels may be associated with restlessness, sensitivity to noise, poor attention span, poor concentration, irritability, aggressiveness, and anxiety.

From a parent- “Our daughter also used to look in the mirror all the time - really up close and wanting to look at herself and poke her eyes. I was so worried about it that I finally put pepper juice on her fingers so she would stop. I know that sounds awful - but she had really gotten bad. Dr. Shaw said that their eyes are hurting so much from lack of calcium. He recommended 1000mg. daily - our daughter was about 43 pounds at the time. I started giving it to her and her eye poking stopped and I noticed that so many of her other stimming behaviors also decreased.”

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REFERENCES

1. Hediger ML, England LJ,Molloy CA, Yu KF, Manning-Courtney P, Mills JL. Reduced bone cortical thickness in boys with autism or autism spectrum disorder. J Autism Dev Disord. 2008;38(5):848–856

2. Coleman, M. Clinical presentations of patients with autism and hypocalcinuria. Develop. Brain Dys. 7: 63-70, 1994

3. Caudarella R, Vescini F, Buffa A, Stefoni S. Citrate and mineral metabolism: kidney stones and bone disease. Front Biosci. 2003 Sep 1;8:s1084-106.

4. M. Mousain-Bosc et al Improvement of neurobehavioral disorders in children supplemented with magnesium-vitamin B6 II. Pervasive developmental disorder-autism. Magnesium Research 2006;19(1): 53-62

5. Fleming, CR, et al.  The importance of urinary magnesium values in patients with gut failure.  Mayo Clinic Proceedings. 1996 Jan;71(1):21-4

Vitamin D and Depression

James Greenblatt, M.D.

Vitamin D was thought to be of use only in preventing rickets and osteomalacia. Accumulating evidence, however, has demonstrated that vitamin D does much more, influencing the health and function of tissues and organs throughout the body. Vitamin D is an important nutrient for our physical health, but many people are unaware of how critical this vitamin is for maintaining our mental health. In this article, we will explore the evidence-based research on vitamin D and depression. The next article will explore the effects of vitamin D on psychosis and schizophrenia.

Vitamin D is categorized as a hormone because of its paracrine, autocrine, and endocrine functions, and it can be acquired through food or exposure to the sun. Vitamin D can be found in high amounts in fatty fish and also in milk, yogurt, orange juice and cereals, and dietary supplements. A sufficient amount of vitamin D can also be produced from 5-15 minutes of daily exposure to sunlight.

Vitamin D2, or ergocalciferol, is only made by plants and vitamin D3, or cholecalciferol, is created when ultraviolet light hitting the skin photochemically converts cholesterol to vitamin D. Serum 25-hydroxyvitamin D [25(OH)D] is a biological marker used to reliably measure the levels of both forms of vitamin D. Among its many functions, vitamin D is important for absorbing calcium, maintaining calcium homeostasis in tissues, growth of bones and teeth, properly functioning neurons and glial cells, preventing rickets and osteomalacia, influencing tissues and organs, preventing psoriasis, muscle pain, weakness, elevated blood pressure, some forms of cancer, and autoimmune disease, and preserving mental health.

Recent studies have advanced our understanding of vitamin D and its effect on the brain. There are vitamin D receptors in neurons and glial cells in the brain. Specifically, research suggests vitamin D may act on particular regions of the brain important in the development of depression, including the prefrontal cortex, hippocampus, cingulate gyrus, thalamus, hypothalamus, and substantia nigra. Moreover, it has also been discovered that genetic variations of vitamin D receptors are associated with depression. Recent research shows vitamin D controls the transcription of over one thousand genes involved in neurotrophic and neuroprotective effects, including the maintenance and development of neurons. In addition, vitamin D may also stimulate the release of neurotrophins, a family of proteins that function to protect and stimulate the growth of neurons.

In a recent study, Polak et al. investigated the association between vitamin D levels and depressive symptoms in 615 young adults. Subjects in the lowest quartile of vitamin D levels were more likely to report having symptoms of depression than those in the highest quartile, suggesting that vitamin D deficiency is a potential predictor of depression. Similarly, in a study on previously deployed military personnel who committed suicide, Umhau et al. found that subjects in the lowest octile of vitamin D levels had the highest risk of suicide. Milaneschi et al. found a comparable effect in the elderly population, with low levels of vitamin D correlating with a significantly higher risk of developing depression. In another study with adolescent participants, Toppanen et al. measured vitamin D levels and depressive symptoms in the same group of children at 9.8, 10.6, and 13.8 years old. Interestingly, higher levels of vitamin D at age 9.8 predicted lower levels of depression at age 13.8, suggesting an association between low levels of vitamin D and early onset depression.

Bertone-Johnson et al., performed a cross-sectional study on 81,189 older women and found an inverse association between vitamin D levels and depressive symptoms in the postmenopausal women. In another study, Lee et al. found that lower vitamin D levels were associated with depression in a population of 3,369 European men. A study by Black et al. came to the same results in a population of young adult males.

Vitamin D supplements have also been found to enhance positive moods. In a study by Allen et al., healthy subjects were given 800 IU, 400 IU, or no vitamin D during five days of winter. The results of their study showed that vitamin D was able to significantly enhance positive affect and also reduce negative affect. Taken together, these diverse studies suggest an indisputable connection between vitamin D deficiency and depression across all age groups and genders.

Biochemical individuality plays a substantial role in vitamin D status. Although environmental factors, such as nutrition and sun exposure, are considered the major determinants of vitamin D status, genetics are responsible for a large portion of the variation seen in serum 25-hydroxyvitamin D. A Swedish study involving 204 same-sex twins between the ages of thirty-nine and eighty-five years living at northern latitude 60 degrees found that genetic factors were responsible for one-fourth of the variation in serum 25-hydroxyvitamin D, independent of season. During the summer season alone, genetics was responsible for half of the variability in 25-hydroxyvitamin D.

Vitamin D levels between 20 and 30 ng/mL have been traditionally accepted as normal and healthy. We now know that this range is too low, and even people who were thought to be safely in the middle of range may need vitamin D supplementation. Given the quirks of biochemical individuality, some people in the upper reaches may need even more. I prefer to see a 25-hydroxyvitamin D between 40 and 60 ng/mL in my patients. The best way to determine vitamin D deficiency is through serum blood testing which should also be done twice a year.

Research literature supports a link between vitamin D and depression; however, the exact mechanisms are unclear. The research has not yet established whether low levels of vitamin D cause depression, or whether depression causes low levels of vitamin D. New research is continually emerging on the importance of vitamin D in sustaining mental health. In one 2012 study, adolescents in a mental health facility who were vitamin D deficient were 3½ times more likely to have psychotic features when compared to those with sufficient vitamin D levels. We'll explore the exciting research implicating vitamin D's role in other mental illnesses such as psychosis and schizophrenia in the next newsletter.

Clinical References

• Anglin R, Samaan Z, Walter S et al. Vitamin D deficiency and depression in adults: systematic review and meta analysis. British Journal of Psychiatry, 2013.

• Bertone-Johnson ER, Powers SI, Spangler L et al. Vitamin D Supplementation and Depression in the Women's Health Initiative Calcium and Vitamin D Trial. Am J Epidemiol 2012; 176(1):1-13.

• Bertone-Johnson ER, Powers SI, Spangler L, et al. Vitamin D intake from foods and supplements and depressive symptoms in a diverse population of older women. Am J Clin Nutr. 2011 Oct;94(4):1104-12.

• Bertone-Johnson ER. Vitamin D and the occurrence of depression: causal association or circumstantial evidence? Nutr Rev. 2009 Aug;67(8):481-92.

• Black LJ, Jacoby P, Allen KL, et al. Low vitamin D levels are associated with symptoms of depression in young adult males. Aust N Z J Psychiatry 2014 May;48(5):464-71.

• Dean A J, Bellgrove M A, Hall T et al. Effects of vitamin D supplementation on cognitive and emotional functioning in young adults–a randomised controlled trial. PLoS One. 2011;6(11):e25966

• Gracious, BL, Finucane, TL, Friedman-Campbell, M. et al. Vitamin D deficiency and psychotic features in mentally ill adolescents: A cross-sectional study. BMC Psychiatr. 2012; 12: 38.

• Han B, Lyu Y, Sun Y et al. Low serum levels of vitamin D are associated with post-stroke depression. European Journal of Neurology Dec 2014. [E-pub ahead of print].

• Jorde, M. Sneve, Y. Figenschau, J et al. Effects of vitamin D supplementation on symptoms of depression in overweight and obese subjects: randomized double blind trial. J Intern Med. 2008;264(6):599-609.

• Lansdowne AT & Provost SC. Vitamin D3 enhances mood in healthy subjects during winter. Psychopharmacology (Berl) 1998 Feb;135(4):319-23

• Lee DM, Tajar A, O'Neill TW, et al. Lower vitamin D levels are associated with depression among community-dwelling European men. J Psychopharmacol 2011 Oct;25(10):1320-8.

• Polak MA, Houghton LA, Reeder AI, et al. Serum 25-hydroxyvitamin D concentrations and depressive symptoms among young adult men and women. Nutrients 2014 Oct 28;6(11):4720-30.

• Toffanello ED, Sergi G, Veronese N, et al. Serum 25-hydroxyvitamin d and the onset of late-life depressive mood in older men and women: the Pro.V.A. study. J Gerontol A Biol Sci Med Sci 2014 Dec;69(12):1554-61.

• Tolppanen AM, Sayers A, Fraser WD, et al. The association of serum 25-hydroxyvitamin D3 and D2 with depressive symptoms in childhood--a prospective cohort study. J Child Psychol Psychiatry 2012 Jul;53(7):757-66.

• Umhau JC, George DT, Heaney RP, et al. Low Vitamin D Status and Suicide: A Case-Control Study of Active Duty Military Service Members. PLoS One 2013;8(1):e51543.

• Yue W, Xiang L, Zhang YJ, et al. Association of serum 25-hydroxyvitamin D with symptoms of depression after 6 months in stroke patients. Neurochem Res. 2014 Nov;39(11):2218-24.

The Role of Vitamins, Antioxidants, and Anti-Inflammatories in Breast Cancer Prevention and Treatment

Terri Hirning

October is Breast Cancer Awareness Month. As such, we would like to take a moment to focus on how nutritional and supplement therapy can play a role in the prevention and treatment of cancer. When we look at how antioxidants impact cancer, we can see that there is scientific documentation of reduced development of breast cancer in those with high dietary intake of antioxidants. One study in late 2014 titled The Rotterdam Study provides this information: "These results suggest that high overall dietary antioxidant capacity are associated with a lower risk of breast cancer."1 Women who had higher rates of antioxidant intake via diet were less likely to develop breast cancer. What about those who already had breast cancer? Could it help with treatment? A March 2014 issue of Anticancer Research featured a study showing the use of lycopene and beta-carotene in cell death of human breast cancer cell lines. "Our findings show the capacity of lycopene and beta-carotene to inhibit cell proliferation, arrest the cell cycle in different phases, and increase apoptosis."2 Vitamin C has also been studied in terms of its potential impact on breast cancer deaths and has been shown to have a positive effect on mortality rates. "Dietary vitamin C intake was also statistically significantly associated with a reduced risk of total mortality and breast cancer-specific mortality."3

If we can look at the data and determine that higher intake of antioxidants and nutrients can not only reduce development of breast cancer but can also positively impact the mortality rates of cancer, the question then becomes how do we encourage our patients and clients to incorporate these into their diets with higher frequency? We must educate them on the role antioxidants play and the resources available to obtain them, whether from foods or supplements. For example, lycopene is a nutrient that is highlighted for its anticancer properties, specifically in reference to breast cancer. Lycopene is a carotenoid that gives many fruits and vegetables their red color. Unlike other carotenes, lycopene does not get converted into vitamin A. The top 10 sources of dietary lycopene are:

• Guava

• Watermelon

• Tomatoes (cooked)

• Papaya

• Grapefruit

• Sweet Red Peppers (cooked)

• Asparagus (cooked)

• Red (purple) cabbage

• Mango

• Carrots

Continued from BioMed Today:

Encouraging patients to incorporate more foods with lycopene, like those listed above, into their diets is one component. Supplements can also be suggested as a potential option. This is especially true in the case of vitamin D, for which there are many studies showing its role in the prevention of cancers. Adequate vitamin D is being revealed as a critical factor for preventing many diseases, including breast cancer, today.8 "Case-control studies and laboratory tests have consistently demonstrated that vitamin D plays an important role in the prevention of breast cancer."9 Unfortunately due to a variety of reasons, many people are deficient in vitamin D which then can then compromise optimal health. Testing for vitamin D levels, ideally twice a year, is a great way to monitor this critical nutrient and help your patients optimize their health and wellness. Supplementation can then also be recommended to optimize levels. Another promising resource for warding off disease and cancer is curcumin, the extract of the turmeric root. Because of its potent antioxidant and antimicrobial properties, it is being studied extensively for its potential in cancer treatment. The American Cancer Society's website has this to say about it: "Curcumin can kill cancer cells in laboratory dishes and also slows the growth of the surviving cells. Curcumin has been found to reduce development of several forms of cancer in lab animals and to shrink animal tumors."4 The typical therapeutic dose, between 3 and 10 grams per day, exceeds what is normally used in cooking and obtained through dietary consumption so a supplement would be most effective.

Could another reason for the efficacy of curcumin on cancer cell death be its potent anti-inflammatory properties? Curcumin has been studied widely for both its safety and anti-inflammatory potential.5,6 "The laboratory studies have identified a number of different molecules involved in inflammation that are inhibited by curcumin including phospholipase, lipooxygenase, cyclooxygenase 2, leukotrienes, thromboxane, prostaglandins, nitric oxide, collagenase, elastase, hyaluronidase, monocyte chemoattractant protein-1 (MCP-1), interferon-inducible protein, tumor necrosis factor (TNF), and interleukin-12 (IL-12)."7 We see science validating the role our lifestyle has in development of cancer. Diet, exercise, supplementation, our stress level, and other factors all contribute to the whether or not we develop disease and also to our ability to reverse it. It is important to find ways to offer a variety of prevention and treatment options that work with our patients' lifestyles.

Clinical References:

• Pantavos A, Ruiter R, Feskens E, E deKeyser C, Hofman A, H Stricker B, H Franco O, C Kiefte-deJong J (2014). Total dietary antioxidant capacity, individual antioxidant intake and breast cancer risk: The rotterdam study, International Journal of Cancer. 2014 Oct 4. doi: 10.1002/ijc.29249. [Epub ahead of print]

• Gloria NF, Soares N, Brand C, Oliveira FL, Borojevic R, Teodoro AJ (2014).Lycopene and beta-carotene induce cell-cycle arrest and apoptosis in human breast cancer cell lines, Anticancer Research. 2014 Mar;34(3):1377-86.

• Harris HR, Orsini N, Wolk A (2014). Vitamin C and survival among women with breast cancer: a meta-analysis,European Journal ofCancer. 2014 May;50(7):1223-31. doi: 10.1016/j.ejca.2014.02.013. Epub 2014 Mar 7.

• Turmeric (2012). Retrieved on October 5, 2014 from Link

• Chainani-Wu NJ (2003). Safety and anti-inflammatory activity of curcumin: a component of tumeric (Curcuma longa), Journal of Alternative and Complementary Medicine. 2003 Feb; 9(1):161-8.

• Jurenka, JS (2009). Anti-inflammatory Properties of Curcumin, a Major Constituent of Curcuma longa: A Review of Preclinical and Clinical Research, Alternative Medicine Review. Volume 14, Number 2, 2009.

• Nita Chainani-Wu (2003). The Journal of Alternative and Complementary Medicine. February 2003, 9(1): 161-168. doi:10.1089/107555303321223035.

• Vitamin D and Cancer Prevention (2013). Retrieved on October 5, 2014 from http://www.cancer.gov/cancertopics/factsheet/prevention/vitamin-D

• Walentowicz-Sadłecka M, Sadłecki P, Walentowicz P, Grabiec M (2013). The role of vitamin D in the carcinogenesis of breast and ovarian cancer, Ginekologia Polska. 2013 Apr;84(4):305-8.

Rickets and eye-poking in autism associated with calcium deficiency

William Shaw Ph.D

I strongly disagree with the assertion by some individuals in the autism field that calcium is a problem to individuals on the autistic spectrum. Failure to provide adequate calcium is very dangerous and could lead to the loss of the eyes due to severe eye-poking behavior. Calcium deficiency can be a severe problem in normal children on a milk free diet since milk is a significant source of protein, vitamin D, and calcium needed for strong bones and teeth. Some physicians have reported rickets (1), a severe bone deformity, occurs in children with autism on the gluten and casein free diet who did not receive added calcium supplements. Calcium and vitamin D supplementation is essential to children on a casein free diet since most children with autism do not eat substantial amounts of other calcium-rich foods. Use of milk substitutes like B-Unique® provides adequate calcium, protein, and fat comparable to whole milk without the presence of casein and lactose that are problematic in most children with autism.

Children with autism may have an even more severe problem with calcium deficiency. Mary Coleman, M.D. (2) reported that children with autism who are calcium deficient are much more likely to poke out their eyes and a substantial number of children with autism have done so. I have talked to numerous parents of children with autism that began to touch their eyes after starting the casein-free diet. This abnormal behavior is associated with low urine calcium; blood calcium levels were usually normal. Treatment with calcium supplementation prevents this behavior. (I suspect that this behavior is due to increased eye pain due to high substance P or to deposits of oxalate crystals in the eye. Low calcium may act to intensify this pain and poking out the eye relieves the pain.) Dr. Coleman also found that speech developed very quickly after calcium supplementation in a portion of mute children with autism who had low urine calcium. Parathyroid hormone, calcitonin, and vitamin D were all normal in patients with autism but all of them had low urine calcium. In one case, according to a parent who contacted me, her child with autism persisted in poking at the eyes even after one eye had been poked out and surgically replaced. Calcium supplementation stopped this behavior immediately. I am aware of many other children with eye-poking behavior in which calcium supplements stopped this behavior in less than two days. Verbal autistic children say that their eye pain is severe and that calcium supplementation stopped their pain quickly. The urine calcium and magnesium tests will soon be a part of the Organic Acids Test offered by The Great Plains Laboratory, Inc.

It is important that calcium, magnesium, and zinc be in balance for optimal nutrition. Vitamin D supplementation may also be needed when milk is eliminated unless other sources of vitamin D are included in the diet or the child is exposed to adequate sunlight. Children with autism also need additional calcium to prevent oxalate deposition in the tissues. Although sardines and dark leafy greens like spinach, kale, turnips, and collard greens are high in calcium, all of these foods except sardines are high in oxalates. High oxalates can be fatal if formed in the renal tract. Oxalates in the urine are much higher in individuals with autism than in normal children. As a matter of fact, 36% of the children on the autistic spectrum had values higher than 90 mmol/mol creatinine, the value consistent with a diagnosis of genetic hyperoxalurias while none of the normal children had values this high. 84% of the children on the autistic spectrum had oxalate values outside the normal range (mean ± 2 std dev). None of the children on the autistic spectrum had elevations of the other organic acids (glyceric and glycolic acids) associated with genetic diseases of oxalate metabolism, indicating that oxalates are high due to external sources. When calcium is taken with foods that are high in oxalates, oxalic acid in the intestine combines with calcium to form insoluble calcium oxalate crystals that are eliminated in the stool. This form of oxalate cannot be absorbed into the body. When calcium is low in the diet, oxalic acid is soluble in the liquid portion of the contents of the intestine (called chyme) and is readily absorbed from the intestine into the bloodstream. If oxalic acid is very high in the blood being filtered by the kidney, it may combine with calcium to form crystals that may block urine flow and cause severe pain. However, such crystals may also form in the bones, joints, blood vessels, lungs, eyes, skin, heart, thymus, skeletal muscle, joints, fat, teeth, mouth, nerves, and even the brain. In addition, oxalate crystals in the bone may crowd out the bone marrow cells, leading to anemia and immunosuppression. Calcium citrate is the best source of calcium to prevent oxalate absorption because citrate ion blocks the absorption of oxalates in the intestinal tract (3). A combination of calcium citrate and magnesium citrate is the best form of supplement to provide calcium and magnesium needs while preventing excess oxalate buildups in the body.

Clinical References:

• 1. Hediger ML, England LJ,Molloy CA, Yu KF, Manning-Courtney P, Mills JL. Reduced bone cortical thickness in boys with autism or autism spectrum disorder. J Autism Dev Disord. 2008;38(5):848–856

• 2. Coleman, M. Clinical presentations of patients with autism and hypocalcinuria. Develop. Brain Dys. 7: 63-70, 1994

• 3. Caudarella R, Vescini F, Buffa A, Stefoni S. Citrate and mineral metabolism: kidney stones and bone disease. Front Biosci. 2003 Sep 1;8:s1084-106.

The Implications of Low Cholesterol in Depression and Suicide

James M. Greenblatt, M.D.

For the last quarter century, we have been told that cholesterol is dangerous for our health and were advised to avoid it in order to live a healthier life. However, cholesterol is essential in maintaining good mental health. The brain is the most cholesterol-rich organ in the body, and depriving the brain of essential fatty acids and cholesterol can lead to detrimental health problems. Lower levels of cholesterol in the blood are associated with a heightened risk of developing major depressive disorder, as well as an increased risk of death from suicide. A study published in the Journal of Psychiatric Research found that depressed men with low total cholesterol levels (less than 165 milligrams per deciliter [mg/dL]) were seven times more likely to die prematurely from unnatural causes such as suicide and accidents.

Most recently, the continued allegation that cholesterol is dangerous came under scrutiny. A meta-analysis published in the March 2014 issue of Annals of Internal Medicine found that there's not enough evidence supporting the claim that saturated fat increases the risk of heart disease. After reviewing 72 different studies, researchers did not find that people who ate higher levels of saturated fat had more heart disease than those who ate less. Researchers came to the conclusion that instead of avoiding fats, which are essential to maintaining brain health, scientists are identifying the real villains as sugar and highly processed foods.

Low Cholesterol and Depression

Several studies have linked low cholesterol levels to an increased risk of developing depression. Consider the following examples:

• A 1993 paper published in the Lancet reported, "Among men aged seventy years and older, categorically defined depression was three times more common in the group with low total plasma cholesterol . . . than in those with higher concentrations."

• A 2000 study published in Psychosomatic Medicine, researchers compared cholesterol levels to depressive symptoms in men ranging in age from forty to seventy. They found that men with long-term, low total cholesterol levels "have a higher prevalence of depressive symptoms" compared to those with higher cholesterol levels.

• Women with low cholesterol levels are also vulnerable to depression. In 1998, Swedish researchers reported the results of their examination of cholesterol and depressive symptoms among 300 healthy women, ages thirty-one to sixty-five, in and around Stockholm. Women in the lowest cholesterol group (the bottom tenth percentile) suffered from significantly more depressive symptoms than did the others.

• A 2001 study published in Psychiatry Research looked at primary care patients in Ireland, finding that low levels of cholesterol were linked to higher ratings on depression rating scales.

• Italian researchers measured the cholesterol levels of 186 patients hospitalized for depression and found an association between low cholesterol and depressive symptoms.

This research is supported by other studies, including a 2008 meta-analysis, which found that higher total cholesterol was associated with lower levels of depression. A 2010 study published in The Journal of Neuropsychiatry & Clinical Neurosciences looked at the levels of HDL in depressed people and found that low levels of HDL were linked to "long-term depressive symptomatology."

Low Cholesterol and Suicide

Suffering through a depressive episode can be very difficult, and one of the great fears is that someone in the throes of depression does not see any point in continuing to live.

Early evidence of a link between low cholesterol and suicide came from the Multiple Risk Factor Intervention Trial study, a large-scale, long- term look at various health factors involving hundreds of thousands of volunteers. Data from the study was analyzed by researchers from the University of Minnesota, who found that people with total cholesterol levels lower than 160 mg/dL were more likely to commit suicide than those with higher cholesterol levels. Other studies are equally alarming:

• A 2008 study looked at forty men who were hospitalized due to bipolar disorder. Twenty had attempted suicide at some point in the past, and the other twenty had not. Both cholesterol and blood fat levels were lower, on average, among those who had attempted suicide.

• A paper published in the Journal of Clinical Psychiatry in the same year reported the results of an examination of cholesterol levels in 417 patients who had attempted suicide at some point, 155 hospitalized psychiatric patients who had not, and healthy controls. Results of the study suggest that low cholesterol may be associated with suicide attempts.

• The suicidal method of choice, self-inflicted fatal gun wound versus pills, for example, may also be related to cholesterol levels. A2008 study published in Psychiatry Research compared nineteen people who had attempted suicide using violent methods to sixteen who had attempted to kill themselves nonviolently, as well as to twenty healthy controls. The researchers found that "violent suicide attempters had significantly lower total cholesterol and leptin levels compared with those with nonviolent suicide attempts."

The connection between low cholesterol and suicide is highlighted in a 2004 study, which concluded that a low total cholesterol level can be used as an indicator of suicide risk. This study, involving suicide attempters with major depressive disorder, nonsuicidal depressed patients, and normal controls, found significant differences in cholesterol levels among the various groups.

The average total serum cholesterol level was 190 mg/dL among the normal controls, 180 mg/dL in nonsuicidal depressed group, and 150 mg/dL among the suicidal depressive patients. This study showed that the total cholesterol level can be used to gauge possible suicide risk (less than 180 mg/dL) and probable risk (150 mg/dL and lower).

Suicide is not the only type of violence associated with lower cholesterol levels. Homicide and other violence committed against others is also associated with low cholesterol. Swedish researchers compared one-time cholesterol measurements on nearly eighty thousand men and women, ranging in age from twenty-four to seventy, to subsequent arrests for violent crime. The researchers reported that "low cholesterol is associated with increased subsequent criminal violence."

What's the Cholesterol-Depression Link?

There is strong scientific evidence indicating that low cholesterol and suicide, particularly violent suicide, are linked. The vast majority of studies linking low cholesterol to depression, suicide, and violence looked at the serum cholesterol level. But what about the amount of cholesterol in the brain?

Canadian researchers were the first to examine this question in their 2007 study published in the International Journal of Neuropsychopharmacology. The researchers measured and compared the cholesterol content in various parts of the brains of forty-one men who had committed suicide and twenty-one men who had died of other, sudden causes that had no direct impact on the brain. The results were intriguing: When the suicides were categorized as violent or nonviolent, those who had committed violent suicide were found to have less cholesterol than the others in the gray matter of their brains. This was seen specifically in the frontal cortex, a part of the brain that handles "executive functions," including processes involved in planning, cognitive flexibility, abstract thinking, initiating appropriate actions and inhibiting inappropriate actions, and selecting relevant sensory information. The frontal cortex essentially controls the ability to make good decisions.

Cholesterol is a critical precursor to many essential physiological molecules in the human body that directly and indirectly affect our moods and optimal brain function. Some researchers theorize that low levels of cholesterol alter brain chemistry, suppressing the production and/or availability of the neurotransmitter serotonin. Cholesterol is essential for the synthesis of all steroid and sex hormones, including DHEA, testosterone, and estrogen. Cholesterol is also needed in the synthesis of vitamin D.

Clinically low cholesterol is a significant variable in the treatment and recovery from mood disorders. A simple blood test looking at total cholesterol can reflect multiple factors influencing treatment. In my clinical practice for the past 20 years, I have found that low cholesterol (<130) has significant implications for what is referred to as "treatment-refractory" depression. This refers to patients who have failed to recover from traditional antidepressant medications. Treatment-refractory patients often struggle with intense suicidal ideation and aggressive behavior. Often, we are able to determine that low cholesterol is genetic, as there are other members in the family who also have low cholesterol levels, despite eating a diet rich in cholesterol and saturated fats. For individuals with low cholesterol, a diet with adequate cholesterol and saturated fats is highly recommended in order to replenish cholesterol levels, although supplemental cholesterol may also be needed for many.

New Beginning's Sonic Cholesterol supplement provides 250 milligrams of cholesterol per capsule. Individuals with low cholesterol levels may take between two to six capsules per day in order to restore adequate cholesterol levels for optimal brain function. Cholesterol repletion is often slow and can take many months. Once cholesterol levels are normalized, we often see an improvement in symptoms and a decreased dependency on medications. It is quite striking to consistently witness the high correlation between cholesterol levels and behavioral and mood symptoms.

For information about cholesterol supplementation, contact New Beginnings Nutritionals.

Conclusion

There is a growing amount of research looking at the use of essential fatty acids, particularly omega-3's in psychiatry, but we often overlook cholesterol. Low levels of cholesterol and essential fatty acids are intimately linked to depression. Understanding the consequences of deficiencies in essential fats and cholesterol is important for the effective treatment of depression. Whether it is drug induced, genetic, or a result of dietary patterns, low cholesterol impairs optimal brain function and often prevents successful recovery from chronic depression.

Clinical References:

• 1. Hediger ML, England LJ,Molloy CA, Yu KF, Manning-Courtney P, Mills JL. Reduced bone cortical thickness in boys with autism or autism spectrum disorder. J Autism Dev Disord. 2008;38(5):848–856

• 2. Coleman, M. Clinical presentations of patients with autism and hypocalcinuria. Develop. Brain Dys. 7: 63-70, 1994

• 3. Caudarella R, Vescini F, Buffa A, Stefoni S. Citrate and mineral metabolism: kidney stones and bone disease. Front Biosci. 2003 Sep 1;8:s1084-106.

Cholesterol Balance – A Major Factor in Many Chronic Disorders

William Shaw, PhD

Cholesterol Balance – Deficiency & Excess

Low cholesterol has been connected to depression, anxiety, bipolar disorder and statistically higher frequency of violent behavior, suicide, Parkinson’s disease, and cancer mortality. Susceptibilities to tuberculosis and gastrointestinal infections are also associated with lower cholesterol levels. Most significantly, the death rate is doubled in older adults with lower total cholesterol and stroke and cataracts rates are higher.

Cholesterol is a sterol essential to life and is found in every animal cell. Cholesterol is part of our cellular structure and protects our tissues. Many people fear and focus on high cholesterol levels, yet never focus on low cholesterol levels, which can have negative health effects. Like everything in nature, balance is the key.

High cholesterol is statistically associated with greater risk of cardiovascular disease (CVD), but less well known is the association of low cholesterol with poor health and many chronic disorders. Recent studies have suggested strongly that lower cholesterol does not guarantee a long life or high quality of life.

The Great Plains Laboratory, Inc. (GPL) offers the Advanced Cholesterol Profile. This profile is used to determine whether a cholesterol deficiency is present or if cholesterol is elevated. This profile also determines if the body is eliminating potentially toxic homocysteine and determines risk factors for vascular disease and/or neurological disease.

Benefits of Cholesterol

Cholesterol serves several important roles in metabolism: it is a key constituent of all cell membranes and provides the structural framework of vitamin D and adrenal and sex hormones, as well as for bile acids which help digest fat and increase absorption of fat soluble vitamins. Most cholesterol is made in the liver and is so crucial to metabolism that, if necessary, it can be synthesized from either fatty acids or glucose. 

The Brain is the Most Cholesterol-Rich Organ in the Body

Cholesterol synthesized in the brain is the primary component of the myelin that surrounds each nerve cell as a protective sheath. Loss of myelin from disease or injury inevitably causes neurological damage. Both neurons and glial (support) cells in the central nervous system (CNS) contain unbound cholesterol as an integral part of their cell membranes.

Cholesterol & Cardiovascular Disease

High cholesterol may be associated with the onset of CVD, but cholesterol may be deposited as a “patch” on inflamed or injured blood vessels, particularly coronary arteries. Macrophages scavenge cholesterol along with other cell debris and may become “foam cells” which accumulate in artery walls and cause atherosclerotic streaks. Assessments of inflammation such as C-reactive protein (test available at GPL) or homocysteine level have been suggested as better predictors of CVD risk.

Homocysteine (Hcy) is a non-protein, non-structural amino acid that is generated by metabolism of methionine, an essential amino acid. Homocysteine can be recycled back to methionine with folic acid and vitamin B-12 as co-factors.

Low Cholesterol Associated with Mental Disorders & Mortality in Elderly

Understanding the health consequences of lower cholesterol has been aided by studying serious genetic disorders that prevent cholesterol synthesis in the body. Low choles-terol has been connected to greater risks of suicide, accidents, violence, and mood disorders, such as depression.

Cholesterol levels may influence serotonin activity in the brain. Serotonin is the neurotransmitter associated with mood, and low serotonin is associated with depression and violent and anti-social behavior. Several theories about how cholesterol levels are related to serotonin levels have been proposed. The simplest effect may be that if cholesterol in the nerve cell membrane is deficient, serotonin cannot properly bind to its receptor. Cholesterol also stabilizes receptors for the social-bonding hormone oxytocin.

In the elderly, studies over several decades have pointed to increased risk of death in the population with the lowest cholesterol. Falling cholesterol in the elderly is a sign of increasing morbidity, with controversy over whether it is a sign of underlying chronic disease or a cause of disease. 

Testing Cholesterol with The Great Plains Laboratory, Inc.

The Advanced Cholesterol Profile is useful for adults whose low cholesterol may put them at risk for mood disorders or infectious disease. Medical historians have noted that tuberculosis has been uncommon in the USA since the Great Depression, during which high cholesterol foods were unavailable to many because of financial hardship. Vegetarians also have a much higher incidence of tuberculosis than meat eaters. Pregnant women with low cholesterol are twice as likely to have premature babies or babies with small heads.

In addition to total cholesterol, the Advanced Cholesterol Profile includes Apolipoprotein A-I and Apolipoprotein B, Lipoprotein (a) , and Homocysteine.

Lipoproteins are enclosures of protein carrying water-insoluble fat (cholesterol and triglycerides) for transport in the bloodstream and through cellular and mitochondrial membranes. Apolipoproteins have a detergent-like structure that allows them to interface on the outside with aqueous blood and with the lipids bound to the inside. These specialized proteins also serve as enzyme co-factors and receptor ligands (receptor interactions control cholesterol synthesis, transport, and metabolism).

Total Cholesterol

Total cholesterol is the same measure in all lipid panels. Low values (generally values less than 4.14 mmol/L* ; 160 mg/dL*) are associated with genetic diseases of cholesterol metabolism. 
In China, where mean cholesterol is much lower than in the Western world, chronic hepatitis B virus infection is ubiquitous. Chronic carriers of hepatitis B, but not individuals with eradicated hepatitis B, have significantly lower total cholesterol than non-carriers, suggesting a cause-effect relationship. Inflammation and higher cholesterol levels are hypothesized to increase the risk of cardiovascular disease (CVD). Genetic diseases of cholesterol and lipid metabolism have been strongly associated with increased CVD.

Apolipoprotein A-I (Apo A-I)
The main protein component of HDL (high density lipoprotein, the so-called “good cholesterol”) accounts for approximately 65% of the total protein content of HDL. Apo A-I triggers the esterification or binding of free cholesterol with long-chain fatty acids. This is the form in which cholesterol can then be transported back to the liver, metabolized, and excreted in bile. Values of Apo A-I have been shown to decrease during infection.

Apolipoprotein B (Apo B)
The main protein component of LDL (low density lipoprotein, the so-called “bad cholesterol”) accounts for approximately 95% of the total protein content of LDL. Apo B is necessary for the reaction with LDL receptors in the liver and on cell walls and is thus involved in transporting cholesterol from the liver to the cells. Recently, the Mind Institute found that low values of Apo B are associated with autism, with the lowest values being found in low-functioning autism. LDL has been found to have protective effects against endotoxins from deadly staphylococcus bacteria.

Lipoprotein (a) (Lp (a))
Lp (a) is a modified version of LDL containing Apo B and a unique protein, apolipoprotein (a) linked by a disulfide bridge. High values have been implicated as a risk factor for cardiovascular disease, Alzheimer’s disease, Crohn’s disease, and rheumatoid arthritis. Low values have also been found in those with autism who have higher levels of Apolipoprotein E epsilon-4 gene variants that are associated with increased risk of Alzheimer’s disease. Lipoprotein (a) is biochemically unrelated to Apolipoprotein A.

Homocysteine (Hcy)
Homocysteine (Hcy) is a sulfur-containing amino acid that is converted back to methionine in a cycle that required B12 and folic acid. Although the role of homocysteine in atherosclerosis is still being studied, high Hcy levels suggest supplementation with folic acid and vitamin B12 may be protective. The genetic disorder homocystinuria is known to cause massive atherosclerosis in younger people, although the mechanism by which homocysteine promotes narrowing and hardening of arteries is unknown. Abnormally high values have been reported in stroke, cardiovascular disease, and in Alzheimer’s disease. The Advanced Cholesterol Profile includes an Hcy level, which is usually a separate blood test.

The Advanced Cholesterol Profile uses FDA-approved diagnostic laboratory reagents, which assures quality results.

* Some countries (Canada, Europe, Middle East, and others) report cholesterol levels using mmol/L while the U.S. and Latin America use mg/dL.