James Greenblatt MD

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.

Beyond the Gut: The Relationship Between Gluten, Psychosis, and Schizophrenia

JAMES GREENBLATT, MD & DESIREE DELANE, MS

Introduction

The National Institutes for Mental Health provide a succinct definition for schizophrenia as periods of psychosis characterized by disturbances in thought and perception and disconnections from reality; however, diagnosis is much less straightforward.  Schizophrenia represents a wide illness spectrum with symptomatic features and severity ranging from odd behavior to paranoia.  With a prevalence rate over the past century holding steady at 1% worldwide and immovably poor patient outcomes, schizophrenia delivers profound relational and societal burdens, proving to be a complex clinical challenge and an unyielding epidemiological obstacle.

Gluten as a Trigger for Psychosis

Although the role of food hypersensitivities in disease pathologies is highly controversial in the medical community, many recognize a parallel rise with dietary evolution in modern history.  Major shifts from ancestral diets largely absent of wheat or dairy to one with these as foundational components generate reasonable arguments on their implications for human health.  Industrialized food systems that streamline the way foods are grown, processed, and stored are often charged with altering their very nature down to its most infinitesimal molecules.  Yet, despite their diminutive size, micronutrients from food are essential to the complex processes and interactions that represent optimal health.

Intolerance to gluten represents one of the most prominent food hypersensitivities arising in recent history, delivering profound impacts to both physical and mental health.  As the most severe reaction to gluten, Celiac Disease (CD) affects a growing population of men and women in the United States.  Unfortunately, an estimated 83% of cases remain undiagnosed or wrongly diagnosed with other conditions. Like other autoimmune diseases, CD is a factor of underlying genetic susceptibility combined with environmental pressures.  Sometimes remaining non-symptomatic for years, CD progressively damages the lining of the intestine, eventually presenting with severe gastrointestinal symptoms including gas, bloating, diarrhea, and constipation.  One of the most dangerous consequences is that digestion and absorption become impaired, resulting in malnutrition and increasing requirements for several key nutrients.  Furthermore, chronic, subtle inflammation keeps the immune system on high alert, promoting an environment of oxidative stress in which free radicals wreak havoc throughout the body.  By elevating the body’s overall inflammatory status, CD and other immune-mediated food allergies trigger not only immediately apparent physical symptoms, but also biochemical imbalances that alter brain function.  Notably, data showing that CD is often incorrectly and inconsistently diagnosed suggests that mental symptoms are often misinterpreted or overlooked.

A separate byproduct of gluten metabolism poses another, possibly more dramatic and direct, threat to brain function.  Gliadorphin, a peptide fragment produced through the breakdown of gluten, directly accesses the brain and attaches to opiate receptors.  Neuropeptides including gliadorphin and casomorphin, a structurally similar byproduct of dairy, mimic and interfere with normal neurotransmitter communication, producing significant mental symptoms ranging from fatigue and brain-fog to hallucinations and aggression.  Like the opiate drugs morphine and heroin, food-derived opiates hold strongly addictive properties as they promote reward, sedation, and satiety.  Sensitive individuals are typically marked by excessive cravings and dependence on food sources of gliadorphin and casomorphin, that manifest in difficulties regulating mood and behavior when levels are depleted.  Fortunately, mental health practitioners have begun to recognize the contribution of neuropeptides in many psychiatric conditions.

Gluten, Gliadorphin, & Schizophrenia

Like Celiac disease, experts agree that schizophrenia has both genetic and environmental contributors, and evidence even suggests that overlapping genetic risk factors may underlie a shared susceptibility for schizophrenia and Celiac disease.  A 2004 Danish case-control study indicated that individuals with a history of Celiac disease may have a 3x greater risk of developing schizophrenia.  Additionally, short-term immune-related exposures during gestation or early life can have long-term consequences for the brain by inducing permanent DNA modifications.  Maternal or post-natal illnesses and infections have all been linked to a greater risk for psychosis and schizophrenia.  Excessive immune activation during these critical developmental periods can also influence the body’s response to potential food allergens.  From the other direction, schizophrenia and psychosis may invoke unique immune mechanisms influencing an individual’s reactivity to gluten. 

Remarkably, the relationship between gluten and psychosis appears to go beyond Celiac disease.  Elevated levels of gliadorphin have consistently been measured in patients with schizophrenia, autism, attention-deficit-hyperactivity disorder, depression, and other psychiatric conditions.  Abnormally low activity of the dipeptidyl peptidase IV (DPP-IV) enzyme, involved in the breakdown of gluten, offers a potential link.  A clinical study in roughly 60 patients with schizophrenia or depression suggested that significant alterations in DPP-IV activity characterized patients with schizophrenia.  The prevalence of elevated gliadorphin and other opiate peptides in psychosis patients has led some researchers to believe that these psychoactive substances carry unique information to the brain that influence disease development.

Without normal breakdown of gliadorphin by DPP-IV, neurotoxic levels accumulate and produce psychoactive effects.  Significant behavioral alterations in animal models given food-based neuropeptides reflect symptoms of psychosis that were reversible by pre-treatment with opiate-blocking drugs.  Human patients with elevated urinary gliadorphin also demonstrate clinical behavioral improvements when gluten and other sources of “dietary morphine” are removed from the diet.  DPP-IV also modulates the activation and proliferation of CD4+ immune cells, providing an additional mechanistic explanation for the excessive inflammation characteristic of both Celiac disease and schizophrenia.  Finally, normal DPP-IV activity depends on adequate zinc and other nutrients, common casualties of poor intestinal function.

A New Approach to Schizophrenia Treatment

Despite evidence-based attempts to address the diverse spectrum of physical and mental impairments associated with schizophrenia, weak progress has been made over the last 100 years.  The rapid, clear clinical responses of antipsychotic drugs introduced in the 1950s and 1960s once appeared to offer miraculous promise to those suffering with psychotic illness.  At least 70 different medications have been developed targeting similar biochemical pathways and are firmly established as first-line therapies.  Modern antipsychotics can be profoundly useful with skillful use in the initial stages of illness, particularly for severe cases.  But it is no secret that these medications are rarely, if ever, totally effective, have no influence on negative or cognitive symptom categories, and bring debilitating side effects requiring further drug interventions.

A growing wealth of theory and data links nutrition and mental health, yet mainstream psychiatry remains stubbornly fixated on the status quo.  Clinical studies suggest that nutrient requirements in schizophrenia patients exceed generally recommended levels, whether due to poor diet, impaired intestinal function, or genetically induced metabolic differences.  A 2018 systematic review by Firth, et al., of 11 studies in early-stage psychosis patients found deficiencies in antioxidants, amino acids, and polyunsaturated fatty acids.  This recent evidence lends significant support for assertive nutrient-based approaches to schizophrenia treatment, particularly as preventive strategies in high-risk patients.

Normal mental processes require tightly-controlled amounts of B-vitamins, antioxidants, lipids, and many other dietary nutrients as key enzymatic components for neural growth, communication, and protection.  On top of the potentially toxic effects of gluten and its byproducts on some individuals, malabsorptive conditions resulting from food sensitivities or Celiac disease further reduce the bioavailability of these critical nutrients to the brain and exacerbate the biochemical imbalances that drive psychiatric illness.  Resulting from this malnourished state, neurotransmitter dysfunction and miscommunication dramatically alter sensory perception and distort a patient’s experience of reality, manifesting in abnormal behavior and social dysfunction. 

Nutritional and other integrative therapies provide the body and brain with optimal and familiar tools for self-healing.  By addressing the origins of symptoms first, medications can be employed as second-tier strategies that support rather than direct treatment.  The treatment paradigm for schizophrenia must be expanded to adopt strategies for early recognition and prevention and incorporate holistic therapies that empower patients to be involved in their recovery.  Long-term dietary changes, including removal of gluten, and nutritional supplements facilitate recovery and promote resilience and self-care.  The integrative care model for mental health care aims not at just the absence of disease, but for healthy minds, bodies, and futures with hope for independence, happiness, and fulfillment.


References

  1. Chien, W. T., & Yip, A. L. (2013). Current approaches to treatments for schizophrenia spectrum disorders, part I: an overview and medical treatments. Neuropsychiatric disease and treatment, 9, 1311.
  2. Chong, H. Y., Teoh, S. L., Wu, D. B. C., Kotirum, S., Chiou, C. F., & Chaiyakunapruk, N. (2016). Global economic burden of schizophrenia: a systematic review. Neuropsychiatric disease and treatment, 12, 357.
  3. Dauncey, M. J. (2013). Genomic and epigenomic insights into nutrition and brain disorders. Nutrients, 5(3), 887-914.
  4. Ellul, P., Groc, L., Tamouza, R., & Leboyer, M. (2017). The clinical challenge of autoimmune psychosis: learning from anti-NMDA receptor autoantibodies. Frontiers in psychiatry, 8, 54.
  5. Firth, J., Rosenbaum, S., Ward, P. B., Curtis, J., Teasdale, S. B., Yung, A. R., & Sarris, J. (2018). Adjunctive nutrients in first‐episode psychosis: A systematic review of efficacy, tolerability and neurobiological mechanisms. Early intervention in psychiatry.
  6. Jungerius, B. J., Bakker, S. C., Monsuur, A. J., Sinke, R. J., Kahn, R. S., & Wijmenga, C. (2008). Is MYO9B the missing link between schizophrenia and celiac disease?. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, 147(3), 351-355.
  7. Lennox, B. R., Palmer-Cooper, E. C., Pollak, T., Hainsworth, J., Marks, J., Jacobson, L., ... & Crowley, H. (2017). Prevalence and clinical characteristics of serum neuronal cell surface antibodies in first-episode psychosis: a case-control study. The Lancet Psychiatry, 4(1), 42-48.
  8. Liang, W., & Chikritzhs, T. (2012). Early childhood infections and risk of schizophrenia. Psychiatry research, 200(2), 214-217.
  9. Maes, M., De Meester, I., Verkerk, R., De Medts, P., Wauters, A., Vanhoof, G., ... & Scharpé, S. (1997). Lower serum dipeptidyl peptidase IV activity in treatment resistant major depression: relationships with immune-inflammatory markers. Psychoneuroendocrinology, 22(2), 65-78.
  10. Maes, M., Scharpé, S., Desnyder, R., Ranjan, R., & Meltzer, H. Y. (1996). Alterations in plasma dipeptidyl peptidase IV enzyme activity in depression and schizophrenia: effects of antidepressants and antipsychotic drugs. Acta Psychiatrica Scandinavica, 93(1), 1-8.
  11. NIMH. (2017). https://www.nimh.nih.gov/health/topics/schizophrenia/raise/what-is-psychosis.shtml. Accessed 09 April 2018.
  12. Salim, S. (2014). Oxidative stress and psychological disorders. Current neuropharmacology, 12(2), 140-147.
  13. Samaroo, D., Dickerson, F., Kasarda, D. D., Green, P. H., Briani, C., Yolken, R. H., & Alaedini, A. (2010). Novel immune response to gluten in individuals with schizophrenia. Schizophrenia research, 118(1), 248-255.
  14. Sun, Z., Cade, J. R., Fregly, M. J., & Privette, R. M. (1999). β-Casomorphin induces Fos-like immunoreactivity in discrete brain regions relevant to schizophrenia and autism. Autism, 3(1), 67-83.
  15. Younger, J., Parkitny, L., & McLain, D. (2014). The use of low-dose naltrexone (LDN) as a novel anti-inflammatory treatment for chronic pain. Clinical rheumatology, 33(4), 451-459.

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


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.

The Role of Heavy Metals and Environmental Toxins in Psychiatric Disorders

James Greenblatt, MD

Every day we are exposed to toxins from our environment. We may ingest lead and copper from drinking water, phosphate from processed food and soda, various synthetic chemicals from plastic food containers, and pesticides from fruits and vegetables. Both natural heavy metals and man-made chemicals disrupt hormones and brain development. The brain, especially the developing brain, is very vulnerable to contaminants because of its large size (relative to total body weight) and its high concentration of fats which serve as a reservoir for toxicants to build up. This article will explain the role that heavy metals and environmental toxins play in ADHD.

In January 2016, President Obama declared a state of emergency in Flint, Michigan where thousands of residents were exposed to high levels of lead in their drinking water. The corrosive water from the Flint River caused lead from old water pipes to leach into the water supply, putting up to 12,000 children at risk of consuming dangerous levels of lead. Lead poisoning can cause irreversible brain damage and even death, and growing children are especially susceptible to its poisonous effects. Even low blood lead levels reduce IQ, the ability to pay attention, motor function, and academic achievement.

Blood lead levels in children have plummeted since the US phased out the use of leaded gas and paint in the 1970’s. Still, 24 million homes in the US contain deteriorated lead paint and elevated levels of lead-contaminated dust. Soil contains lead from air that settled during our previous industrial use. Old toys and toys from China may contain lead-based paint as well. Again, children are especially at risk of lead poisoning in these environments because they are likely to put their contaminated toys or hands in their mouth.

Since lead poisoning causes cognitive, motor, and behavioral changes, it is not surprising that it also causes ADHD. Lead exposure is estimated to account for 290,000 excess cases of ADHD in US children (Braun et al., 2006). A study on 270 mother-child pairs in Belgium found that doubling prenatal lead exposure (measured in cord blood) was associated with a more than three times higher risk for hyperactivity in boys and girls at age 7-8 (Sioen et al., 2013). A larger study on almost 5,000 US children aged 4-15 found children with the highest blood lead levels were over four times as likely to have ADHD as children with the lowest blood lead levels (Braun et al., 2006).

MRI scans from participants of the Cincinnati Lead Study had striking results: childhood lead exposure was associated with brain volume loss in adulthood. Individuals with higher blood lead levels as children had less gray matter in some brain areas. The main brain region affected was the prefrontal cortex which is responsible for executive function, behavioral regulation, and fine motor control (Cecil et al., 2008).

The CDC has set a blood lead level of 5 µg/dL as the reference value to identify children who require case management. However, many studies have shown lead levels <5 μg/dL still pose problems. For instance, researchers assessing 256 children aged 8-10 concluded, “even low blood lead levels (<5 μg/dL) are associated with inattentive and hyperactivity symptoms and learning difficulties in school-aged children” (Kim et al., 2010).

Copper is an essential trace mineral we must consume from our food supply. It is found in oysters and other shellfish, whole grains, beans, nuts, and potatoes. Like lead, copper can leach into the water supply when copper pipes corrode. One of copper’s roles in the body is to help produce dopamine, the neurotransmitter that provides alertness. However, too much copper creates an excess of dopamine leading to an excess of the neurotransmitter norepinephrine. High levels of these neurotransmitters lead to symptoms similar to ADHD symptoms: hyperactivity, impulsivity, agitation, irritability, and aggressiveness. In children with excess copper, stimulant medications don’t work as well and tend to cause side effects (agitation, anxiousness, change in sleep and appetite). Most ADHD medications work by increasing levels of dopamine, intensifying the effects of excess copper. In addition, excess copper blocks the production of serotonin, a mood-balancing neurotransmitter. This triggers emotional, mental, and behavioral problems, from depression and anxiety to paranoia and psychosis.

The neurotoxic effects of excess copper are well known and a few studies have assessed copper’s role in ADHD symptoms. When researchers compared copper levels in 58 ADHD children to levels in 50 control children, they observed that copper levels were higher in ADHD children. ADHD children also had a higher copper-to-zinc ratio that positively correlated with teacher-rated inattention (Viktorinova et al., 2016). Researchers in Belgium measured the heavy metal exposure of 600 adolescents aged 13-17. They found that an increase in blood copper was associated with a decrease in sustained attention and a decrease in short-term memory. This held true even though this population had normal copper levels (Kicinski et al., 2015). 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. Among those in the highest copper tertile, only 35% were responders compared to 77% in the middle copper tertile (Rucklidge et al., 2014).

Phosphate is a charged particle (an electrolyte) that contains phosphorus. Phosphorus is the second most abundant mineral in the body (the first is calcium). Phosphorus is a building block for bones and about 85% of total body phosphorus is found in the bones. Deficiencies are rare because phosphorus is naturally abundant in protein-rich foods like meat, poultry, fish, eggs, milk, and milk products as well as in nuts, legumes, cereals, and grains. Although phosphorus is an essential nutrient, too much can be problematic. The phosphate content of processed foods is much higher than that of natural foods, because phosphates are commonly used as additives and preservatives in food production. Our daily intake of phosphate food additives has more than doubled since the 1990’s (Ritz et al., 2012). Phosphorus, especially the form found in processed meats, canned fish, baked goods, and soda is quickly absorbed into the bloodstream so levels can rise rapidly.

Phosphorus reduces the absorption of other vital nutrients, many of which ADHD children are deficient in to begin with. For instance, too much phosphorus can lower calcium levels. High phosphorus coupled with low calcium intake leads to poor bone health. The typical American diet contains two to four times more phosphorus than calcium and soda is often a major contributor to this imbalance. In the body, phosphorus and magnesium bind together, making both minerals unavailable for absorption. This is most apparent when magnesium consumption is low and intake of phosphorus is high. Researchers have found that adding Pepsi to men’s diet for two consecutive days causes their blood phosphate levels to increase and their magnesium excretion to decrease (Weiss et al., 1992).

In the 1990’s, German pharmacist Hertha Hafer discovered that excess dietary phosphate triggered her son’s ADHD symptoms. Within her book, The Hidden Drug, Dietary Phosphate: Cause of Behavior Problems, Learning Difficulties and Juvenile Delinquency, she presents a low phosphate diet as a treatment for ADHD. A low phosphate diet led to dramatic improvements in her son’s behavior, well-being, and school performance, rendering medication unnecessary. Her family’s ADHD problem was resolved and her son had no further problems as long as he avoided high phosphate foods. Hafer finds that children with mild ADHD can improve simply by removing processed meats and phosphate-containing beverages like soda and sports drinks from their diets (Waterhouse, 2008).

Everyday plastic products contain hormone-disrupting chemicals, such as Bisphenol A (BPA) and phthalates, that can migrate into our body and affect the brain and nervous system. These environmental toxins bind to zinc and deplete zinc levels in the body. Phthalates are synthetic chemicals used to make plastics soft and flexible. Phthalates are used in hundreds of consumer products and humans are exposed to them daily though air, water, and food. Di(2-ethylhexyl) phthalate (DEHP) is the name for the most common phthalate. It can be found in products made with plastic such as tablecloths, floor tiles, shower curtains, garden hoses, swimming pool liners, raincoats, shoes, and car upholstery. Based on animal studies, the Environmental Protection Agency (EPA) has classified DEHP as a “probable human carcinogen.” Such studies have shown that DEHP exposure affects development and reproduction.

Multiple studies have linked phthalates with ADHD. Researchers assessed the urine phthalate concentrations and ADHD symptoms in 261 children aged 8-11. ADHD symptoms (inattention and hyperactivity/impulsivity), rated by the children’s teachers, were significantly associated with DEHP metabolites (breakdown products) (Kim et al., 2009).

Prenatal phthalate exposure is associated with problems in childhood behavior and executive functioning. Third-trimester urines from 188 pregnant women were collected and analyzed for phthalate metabolites. Their children were assessed for cognitive and behavioral development between the ages of 4 and 9. Phthalate metabolites were associated with worse aggression, conduct problems, attention problems, depression, externalizing problems, and emotional control (Engel et al., 2010).

Exposure to DEHP in pediatric intensive care units (PICU) is associated with attention deficits in children. In the hospital, DEHP can be found in and can leach from medical devices such as catheters, blood bags, breathing tubes, and feeding tubes. Researchers in Belgium measured levels of DEHP byproducts in the blood of 449 children aged 0-16 while they were staying in a pediatric intensive care unit. Four years later, the children’s neurocognitive development was tested and compared to that of healthy children. The researchers found that all medical devices inserted into the body actively leached DEHP. Predictably, hospitalized children had very high levels of DEHP byproducts throughout their stay in the intensive care unit. A high exposure to DEHP was strongly associated with attention deficit and impaired motor coordination four years after hospital admission. Phthalate exposure from the PICU explained half of the attention deficit in post-PICU patients (Verstraete et al., 2016).

BPA is another problem chemical which is found in food and drink packaging. Exposure to BPA may be related to behavior problems in children. A 2016 nationwide study of 460 children aged 8-15 found children with higher urinary levels of BPA had over five times higher odds of being diagnosed with ADHD (Tewar et al., 2016). In another study, researchers measured BPA concentration in urine samples from women at 27 weeks of pregnancy then assessed the behavior of their children at age 6-10. There was a significant positive association in boys between prenatal BPA concentration and internalizing and externalizing behaviors, withdrawn/depressed behavior, somatic problems, and oppositional/defiant behaviors. Researchers speculated that BPA may have disrupted maternal thyroid or gonadal hormones which are critical to proper brain development (Evan et al., 2014).

In addition to heavy metals and plasticizers, pesticides can cause ADHD symptoms. The American Academy of Pediatrics notes, “Children encounter pesticides daily in air, food, dust, and soil. For many children, diet may be the most influential source. Studies link early-life exposure to organophosphate insecticides with reductions in IQ and abnormal behaviors associated with ADHD and autism” (Roberts & Karr, 2012).

Among pesticides, insecticides may be the most harmful to humans. Insecticides were first developed during World War II as nerve gases. They work by targeting and destroying acetylcholinesterase, an enzyme that controls the neurotransmitter acetylcholine which plays a role in attention, learning, and short-term memory. In one study of 307 children aged 4-9, researchers found that lower acetylcholinesterase activity in boys was linked to a four times greater risk of poor attention and executive function and a six times greater risk of memory and learning problems (Suarez-Lopez et al., 2013). Organophosphates (OPs) are a common type of insecticide that target the nervous system. Forty different types of organophosphates are in use in the United States.

Scientists in California studied 320 mothers and their children. They evaluated urinary levels of metabolites of OPs when the mothers were pregnant. Then when the children were 3- and 5- years old, they were evaluated for ADHD. At both time points, levels of prenatal OP metabolites were positively associated with attention problems and ADHD. Children with mothers who had the highest levels of the OP metabolites were five times more likely to develop ADHD (Marks et al., 2010).

Even organophosphate exposure at low levels common among US children may contribute to ADHD prevalence. Researchers at Harvard University studied more than 1,000 children aged 8-15 from the general population and found that those with detectable urinary levels of an OP metabolite were nearly twice as likely to be diagnosed with ADHD (Bouchard et al., 2010).


References:

  1. Braun et al (2006). Exposures to environmental toxicants and attention deficit hyperactivity disorder in U.S. children. Environmental Health Perspectives, 114(12), 1904-1909.
  2. Cecil et al. (2008). Decreased Brain Volume in Adults with Childhood Lead Exposure. PLoS Medicine, 5(5), PLoS Medicine, 2008, Vol.5(5).
  3. Engel et al. (2010). Prenatal phthalate exposure is associated with childhood behavior and executive functioning. Environmental Health Perspectives, 118(4), 565-71.
  4. Evans et al. (2014). Prenatal bisphenol A exposure and maternally reported behavior in boys and girls. Neurotoxicology, 45, 91-99.
  5. Kicinski et al. (2015). Neurobehavioral function and low-level metal exposure in adolescents. International Journal of Hygiene and Environmental Health, 218(1), 139-146.
  6. Kim et al. (2009). Phthalates Exposure and Attention-Deficit/Hyperactivity Disorder in School-Age Children. Biological Psychiatry, 66(10), 958-963.
  7. Kim et al. (2010). Association between blood lead levels (< 5 μg/dL) and inattention-hyperactivity and neurocognitive profiles in school-aged Korean children. Science of the Total Environment, 408(23), 5737-5743.
  8. Ritz, et al. (2012). Phosphate additives in food--a health risk. Deutsches Ärzteblatt International, 109(4), 49-55.
  9. Roberts & Karr. (2012). Pesticide exposure in children. Pediatrics, 130(6), E1765-88.
  10. 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.
  11. Sioen et al. (2013). Prenatal exposure to environmental contaminants and behavioural problems at age 7–8years. Environment International, 59, 225-231.
  12. Suarez-Lopez et al. (2013). Acetylcholinesterase activity and neurodevelopment in boys and girls. Pediatrics, 132(6), E1649-58.
  13. Tewar et al. (2016). Association of Bisphenol A exposure and Attention-Deficit/Hyperactivity Disorder in a national sample of U.S. children. Environmental Research, 150, 112-118.
  14. Verstraete et al. (2016). Circulating phthalates during critical illness in children are associated with long-term attention deficit: A study of a development and a validation cohort. Intensive Care Medicine, 42(3), 379-92.
  15. Viktorinova et al. (2016). Changed Plasma Levels of Zinc and Copper to Zinc Ratio and Their Possible Associations with Parent- and Teacher-Rated Symptoms in Children with Attention-Deficit Hyperactivity Disorder. Biological Trace Element Research, 169(1), 1-7.
  16. Waterhouse, J.C. (2008). Issue 6. Review of the Book: The Hidden Drug, Dietary Phosphate: Causes of Behaviour Problems, Learning Difficulties and Juvenile Delinquency (2000). SynergyHN. https://synergyhn.wordpress.com/phosphate
  17. Weiss, G. H., Sluss, P. M., & Linke, C. A. (1992). Changes in urinary magnesium, citrate, and oxalate levels due to cola consumption. Urology, 39(4), 331-333.

DIETARY INFLUENCES ON BEHAVIORAL PROBLEMS IN CHILDREN

James Greenblatt MD, Author of Finally Focused (www.finallyfocusedbook.com), Chief Medical Officer and Vice President of Medical Services at Walden Behavioral Care

It is well known that our food choices play a role in our long-term physical health. It is less recognized that nutrition can have profound effects on our mental health and our behavior. Overall, malnutrition in childhood can affect the brain throughout the lifespan, while specific food components can affect our short-term well-being. Sugar, wheat, and milk are among the most common dietary triggers for ADHD symptoms. Fluctuating blood sugar levels and partially-digested foods can also cause a wide range of symptoms from fatigue to hyperactivity. This article will discuss the dietary influences on behavioral problems in children, review how laboratory testing can be critical in identifying food sensitivities, and how to enhance digestion for maximum absorption of nutrients.

One of the most debated treatments for ADHD is the Feingold Diet, introduced in the early 1970’s by pediatrician and allergist Ben Feingold, MD. He initially suggested that children who are allergic to aspirin (which contains salicylates) may react to artificial food colors and naturally occurring salicylates. The Feingold Diet eliminates artificial food additives like flavorings, preservatives, sweeteners, and colors to reduce hyperactivity. The research over the years on the Feingold Diet has been mixed – some studies show no behavior change and some show increases in hyperactivity when children consume artificial ingredients. A landmark study conducted in the UK on three hundred 3-year-old and 8/9-year-old children in the general population found artificial colors or a sodium benzoate preservative (or both) in the diet resulted in increased hyperactivity (McCann et al., 2007). This study led the European Union to ask manufacturers to voluntarily remove several artificial food colors from foods and beverages or to add a warning label that the artificial food color “may have an adverse effect on activity and attention in children” (Arnold et al., 2012). Conversely, in the US, the FDA reviewed the study and determined that a causal relationship between consumption of color additives and hyperactivity in children could not be definitively established (Arnold et al., 2012).

Genetics often play a role in how a child’s ADHD symptoms are exacerbated. The children most likely to be affected by food additives have a genetic inability to metabolize the compounds. Genetic tests were conducted on the 300 UK children from the artificial food color study. Children with specific variations in the HNMT gene, which helps break down histamine in the body, had stronger behavioral reactions to artificial food colors than children without this variation (Stevenson et al., 2010). This means that in some children, food additives spur the release of histamine that in turn affect the brain.

The Barbados Nutrition Study was a longitudinal case-control study that began in the late 1960’s and investigated the physical, mental, and behavioral developmental effects of infant malnutrition. The 204 participants of this study experienced a single episode of moderate to severe malnutrition during their first year of life. Data was collected on these children through adulthood and compared to data from healthy children. By the end of puberty, all children completely caught up in their physical growth. However, cognitive and behavioral issues persisted into adulthood.

The consequences of malnutrition in infancy manifested in many ways. IQ scores of the children with a history of malnutrition at age 5-11 were significantly lower than those of the control children. 50% of the malnourished children had scores at or below 90 while only 17% of the control children had scores this low (Galler et al., 1983). According to teacher reports, attentional deficits, including shorter attention span, poorer memory, and more distractibility and restlessness, were found in 60% of the malnourished children compared to only 15% of the controls. They also had worse social skills, general health, sleepiness in the classroom, and emotional stability (Galler et al., 1983). When the children were reassessed on these measures at age 9-15, a history of early malnutrition was still associated with behavioral impairment at school, especially attention deficits (Galler & Ramsey, 1989).

Behavior problems reported by teachers when the participants were aged 5-11 significantly predicted conduct problems at age 11-17 (Galler et al., 2012). Age at 5-11, children malnourished as infants had lower performance on 8 out of 9 academic subject areas. 37 children (36 malnourished, 1 control) were below the expected grade for their age (Galler, Ramsey, & Solimano, 1984). Compared to control children, previously malnourished children at age 5-11 had significantly worse scores on parent-rated measures of good behavior (no antagonism between mother and child, obedience), social skills, mother-child relationship, frustration level, eating habits, sleeping habits, and school avoidance. Compared to their siblings, previously malnourished children had significantly worse scores on social skills, good behavior, helpfulness, mother-child interaction, eating habits, toilet training, and language (Galler, Ramsey, & Solimano, 1985). When the children were reassessed on these measures at age 9-15, the same results were seen, especially for aggression and distractibility (Galler & Ramsey, 1989). Problems with self-regulation, displayed as reduced executive functioning and aggression toward peers, persisted through adolescence (Galler et al., 2011).

Years later when the subjects were aged 37-43, attention problems were assessed using an adult ADHD scale and a computerized test of attention-related problems. There was a higher prevalence of attention deficits in the previously malnourished group relative to controls. 69% of the previously malnourished participants had at least one test score that fell within the clinical range for attention disorders (Galler et al., 2012). Previously malnourished participants also had worse educational attainment and income across the entire 40-year study (Galler et al., 2012).

Multiple connections have been made between sugar, hyperactivity, and the risk for ADHD. In group of almost 400 school-age children, researchers found that children with the greatest “sweet” dietary pattern had almost four times greater odds of having ADHD compared to those who ate sweets (ice cream, refined grains, sweet desserts, sugar, and soft drinks) less often (Azadbakht & Esmaillzadeh, 2012). In a similar study on 1,800 adolescents, having a “Western” dietary pattern (higher intakes of total fat, saturated fat, refined sugars, and sodium) more than doubled the odds of an ADHD diagnosis (Howard et al., 2011). Likewise, a study on 986 children, average age 9 years, found a high intake of sweetened desserts (ice cream, cake, soda) was significantly associated with worse inattention, hyperactivity-impulsivity, aggression, delinquency, and externalizing problems. In contrast, a high-protein diet was associated with better scores on these measures. A high level of sweetened dessert consumption was also associated with lower scores on tests of listening, thinking, reading, writing, spelling, and math (Park et al., 2012).

Certain foods may not only influence behavioral and physical symptoms, but may also modify brain activity. When children aged 6-15 with food-induced ADHD consumed provocative foods, they showed an increase in beta activity in frontotemporal regions during EEG topographic mapping of brain electrical activity (Uhlig et al., 1997). Beta waves are involved in normal waking consciousness and tend to have a stimulating effect; while too much beta can lead to anxiety.

A food sensitivity to a protein found in milk or a protein found in wheat is a prevalent but neglected cause of ADHD. Milk and milk products like cheese and butter contain a protein called casein. Casein is different from lactose which is a milk sugar. Grains like wheat, rye, and barley contain a protein called gluten. During digestion, casein becomes casomorphin and gluten becomes gliadorphin. For most people, these proteins are further broken down into basic amino acids. For some with ADHD, they have inactive dipeptidyl peptidase IV, a zinc-dependent enzyme that breaks down both casein and gluten, leaving these opioid peptides substances to build up.

Children with ADHD who have high levels of casomorphin or gliadorphin often have severe, uncontrolled symptoms. Both casomorphin and gliadorphin are morphine-like compounds which attach to opiate receptors in the brain. These substances can act like an addicting drug in susceptible children and cause fatigue, irritability, and brain fog. A child with high levels of casomorphin may have strong cravings for milk products (ice cream, yogurt) and may become irritable when he or she doesn’t eat these types of foods. The Gluten/Casein Peptide Test is a simple urine test that can measure levels of casomorphin and gliadorphin. If a child has high levels of casomorphin or gliadorphin, they should try to eliminate casein or gluten. Supplementation with DPP-IV enzymes can also be beneficial and often required for clinical improvement.

Malnutrition can negatively affect behavior and cognition, but certain nutrients can have detrimental effects on children as well. Louise Goldberg, pediatric dietitian, put it succinctly: “Food allergies and sensitivities can come at children with a one-two punch - first making them agitated, and next robbing them of nutrients that might rein in their behavior” (Peachman, 2013). We are biochemically unique and have different physiological and psychological responses to different foods. The right food for one child may the wrong food for another. For instance, peanut butter on whole wheat toast may be a nutritionally-balanced, energy-boosting snack for one child, while this snack would be harmful to a child who cannot tolerate neither nuts nor wheat. Medical testing can clarify which nutrients a child is sensitive to. Fortunately, eliminating offending substances can rapidly improve physical and behavioral symptoms.

 

References:

Arnold, et al. (2012). Artificial food colors and attention-deficit/hyperactivity symptoms: Conclusions to dye for. Neurotherapeutics: The Journal of the American Society for Experimental NeuroTherapeutics, 9(3), 599-609.

Azadbakht & Esmaillzadeh. (2012). Dietary patterns and attention deficit hyperactivity disorder among Iranian children. Nutrition, 28(3), 242-249.

Galler et al. (1983). The influence of early malnutrition on subsequent behavioral development I. Degree of impairment in intellectual performance. Journal Of The American Academy Of Child And Adolescent Psychiatry, 22(1), 8-15.

Galler et al. (1983). The influence of early malnutrition on subsequent behavioral development II. Classroom behavior. Journal Of The American Academy Of Child And Adolescent Psychiatry, 22(1), 16-22.

Galler & Ramsey. (1989). A follow-up study of the influence of early malnutrition on development: Behavior at home and at school. Journal Of The American Academy Of Child And Adolescent Psychiatry, 28(2), 254-261.

Galler, Ramsey, & Solimano. (1984). The influence of early malnutrition on subsequent behavioral development III learning disabilities as a sequel to malnutrition. Pediatric Research, 18(4), 309-313.

Galler, Ramsey, & Solimano. (1985). Influence of early malnutrition on subsequent behavioral development: V. child’s behavior at home. Journal Of The American Academy Of Child Psychiatry, 24(1), 58-64.

Galler et al. (2011). Early malnutrition predicts parent reports of externalizing behaviors at ages 9-17. Nutritional Neuroscience, 14(4), 138-144.

Galler et al. (2012). Infant malnutrition predicts conduct problems in adolescents. Nutritional Neuroscience, 15(4), 186-192.

Galler et al. (2012). Infant malnutrition is associated with persisting attention deficits in middle adulthood. The Journal Of Nutrition, (4), 788.

Galler et al. (2012). Socioeconomic outcomes in adults malnourished in the first year of life: a 40-year study. Pediatrics, (1), 1.

Howard et al. (2011). ADHD Is Associated with a "Western" Dietary Pattern in Adolescents. Journal of Attention Disorders, 15(5), 403-411.

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Langseth & Dowd. (1978). Glucose tolerance and hyperkinesis. Food And Cosmetics Toxicology, 16(2), 129-133.

McCann et al. (2007). Food additives and hyperactive behaviour in 3-year-old and 8/9-year-old children in the community: A randomised, double-blinded, placebo-controlled trial. The Lancet, 370(9598), 1560-1567.

Niederhofer. (2011). Association of Attention-Deficit/Hyperactivity Disorder and Celiac Disease: A Brief Report. Primary Care Companion For CNS Disorders, 13(3), pii: PCC.10br01104.

Park et al. (2012). Association between dietary behaviors and attention-deficit/hyperactivity disorder and learning disabilities in school-aged children. Psychiatry Research, 198, 468-476.

Stevenson et al. (2010). The role of histamine degradation gene polymorphisms in moderating the effects of food additives on children's ADHD symptoms. The American Journal of Psychiatry, 167(9), 1108-15.

Uhlig et al. (1997). Topographic mapping of brain electrical activity in children with food-induced attention deficit hyperkinetic disorder. European Journal of Pediatrics, 156(7), 557-61.

Lithium: The Untold Story of the Magic Mineral That Charges Cell Phones and Preserves Memory

by James Greenblatt, MD, and Kayla Grossmann, RN

As far as cosmologists can tell, there were only three elements present when the universe was first formed some 13.8 billion years ago: hydrogen, helium, and lithium. As one of the three original elements, lithium is found throughout our atmosphere. The sun, stars, and meteorites burn brightly with the flame of this highly reactive element. On earth, lithium remains a major mineral component of granite rock, and also lingers in significant amounts in sea water, mineral springs, and soils. Lithium has also found its way into our cell phones, electric cars, and holiday fireworks. Every organ and tissue in the human body contains the mineral lithium, with particular importance in brain health.
    
Today, we do not tend to think of lithium as an essential mineral in human physiology and its critical use for expanding technology. Lithium does not evoke visions of stars, peaceful rivers, or strong, healthy bodies. Instead images of lithium are associated with pharmacies, doctor's offices, and back wards of psychiatric hospitals. Lithium is perceived, almost exclusively, as a dangerous drug used to treat severe mental illness with incapacitating side effects. 
    
In a recent review in the New York Times titled "I Don't Believe in God, but I Believe in Lithium," author Jamie Lowe delivered a powerful testimony of her dramatic response to lithium – the drug that alleviated her mania and allowed her to live a normal, happy life. Her article also describes the kidney damage that has forced her to stop lithium and placed her on a waiting list for potential kidney transplant. She provides a unique insight into the life-changing prescriptive benefits of lithium, and the overwhelming fear she has of life without her lithium; a life without her sanity.
    
I have treated thousands of patients with similar backgrounds as Jamie's. This raised the question, how can a medicine provide such life-changing effects on mental health yet cause permanent damage to kidney and often thyroid function?
    
Twenty-five years ago, I attempted to answer this question by looking for the lowest dose of lithium that would alleviate symptoms. Rather than basing my prescription dosage on a number from a lab test that dictated a "therapeutic blood level," I listened to my patients. I began to see that patients on a lower dose of lithium – doses closer to the trace amounts found naturally in the environment – still experienced significant clinical results. 
    
Psychiatry has much to learn from the untold story of one of its oldest drugs.

Lithium as Mineral

Lithium was given its official name by a Swedish chemist named Johan August Arfvedson in 1817. He isolated the element while studying petalite – a rich mineral deposit found in soils – on the remote island of Uto. The unique substance was named lithium after the Greek word lithos, meaning literally "from stone." 
    
Just one year after its initial discovery, researchers noticed that there was something special about this new element. Lithium ore, when ground into a fine powder, turned flames a bright crimson color that intensified to a dazzling white when burning strongly. In addition to being highly reactive, the metal was also lightweight, malleable, and a good conductor of heat and electricity. These characteristics made lithium an immediately desirable commodity for industrial and manufacturing purposes. Since this time it has been used for manifold applications: in aircraft parts, fireworks, heat-resistant cookware, focal lenses, and even the fusion material in power plants. Today, the mineral is most commonly used for building the lithium-ion batteries that power our cell phones, tablets, laptops, and eco-friendly vehicles.
    
Over the past two centuries, scientists have gained a deeper appreciation of this alkali earth metal, which is now known to be relatively common in the earth's upper crust. As the 27th most abundant element, it can be found in rock sediments, salt flats, and mineral springs at varying concentrations throughout the globe. The largest deposits of lithium are salars, or vast saline basins in the deserts of South America. Lithium is also highly concentrated in clay beds and hard rock underground mines dotting Australia, China, and some parts of North America.
    
Lithium is in fact so ubiquitous in these environments that it can readily be found in food and water supplies. The US Environmental Protection Agency has estimated that the daily lithium intake of an average adult ranges from about 0.65 mg to 3 mg. Grains and vegetables serve as the primary sources of lithium in a standard diet, with animal byproducts such as eggs and milk providing the rest. Lithium has even been officially added to the World Health Organization'slist of nutritionally essential trace elements alongside zinc, iodine, and others. 
    
The most frequent source of lithium in the modern diet, however, is tap water. Depending on geographical location, drinking water contains substantial amounts of naturally occurring lithium. According to environmental surveys, water with high mineral content can translate to 2 mg or so of lithium per day. 
    
There has been little research on the specific consequences of lithium deficiency in humans. However, trials in which animals have been put on low-lithium diets have revealed a gross decrease in reproductive function, lifespan, and lipid metabolism. It is quite possible that lithium deficiency has many other effects on human physiology, but the study of nutritional lithium has been overshadowed by the volatile reputation of high-dose pharmaceutical lithium.

Lithium as Medicine

Official documentation of the medical applications of lithium was first publicized by London doctor Alfred Baring Garrod, who used it to treat patients with gout. After discovering uric acid in the blood of his patients with gout, he wrote about pioneering the use of lithium in his 1859 treatise, The Nature and Treatment of Gout and Rheumatic Gout. Between the 1850s and 1890s, several other physicians experimented with lithium treatment because at the time uric acid was viewed as a critical factor in many diseases.
    
Both the medical literature and popular advertisements of the time abounded with praise for lithium. The Sears, Roebuck & Company Catalogue of 1908 advertised Schieffelin's Effervescent Lithia Tablets for a variety of uric acid afflictions. By 1907, The Merck Index listed 43 different medicinal preparations containing lithium. Even soft drink entrepreneur Charles Leiper Grigg understood that there was something special about lithium. In 1929, he unveiled a drink called Bib-Label Lithiated Lemon-Lime Soda with the slogan "It takes the ouch out of the grouch." Hailed for improving mood and curing hangovers, this product was eventually rechristened 7 Up. The "7" supposedly represents the rounded-up atomic weight of the element lithium (6.9), and the "Up" suggests its power to lift spirits. Lithium remained an ingredient of 7 Up until 1950.
    
An Australian psychiatrist, Dr. John Cade, is credited with first experimenting with high doses of lithium citrate and lithium carbonate as a treatment for manic depressive illness in 1949. He observed first in animals and then in human trials that lithium stabilized mood, restored memory, and improved cognitive function, even in his most challenging subjects. Because of his well-structured study and the dramatic results, some historians of medicine consider that Cade ushered in modern psychopharmacology. 
    
Unfortunately, the timing of Cade's treatment successes was ill fated. The very same year, 1949, adverse reaction reports surfaced in the media about patients who were taking lithium chloride in the US. As physicians encouraged patients with heart disease and hypertension to avoid sodium chloride, lithium chloride was marketed as an alternative to sodium chloride in four different preparations: Salti-salt, Milosal, Foodsal, and Westsal. In the late 1940s and early 1950s, physicians around the country released reports of patients who developed lithium poisoning after they had used large, uncontrolled amounts of Westsal. Several deaths were also reported, leading the FDA to ban the use of lithium salt substitutes. "Stop using this dangerous poisoning at once!" exhorted the FDA. Lithium fell out of favor in the American medical community.   
    
Despite this lithium chloride debacle, trials testing the efficacy of lithium carbonate for mania continued in Australia and France. Eventually the research from other countries became so compelling that by the end of the decade, a "lithium underground" had formed of US physicians prescribing lithium in the absence of official FDA approval. Finally, the FDA sanctioned lithium in 1970 as a new investigational drug for use in treatment of acute mania. By this time many other countries had already approved lithium, including France, the UK, Germany, and Italy. In 1974, lithium was finally approved to prevent recurrent mania. 
    
Since the official FDA approval of pharmaceutical-dose lithium, the mineral has proved to be one of the most versatile and successful drugs in psychiatry. According to treatment guidelines, lithium carbonate is recognized as the first-line therapy in patients with bipolar disorder. Recent meta-analyses underscore the superiority of lithium as a prophylactic for both mania and depression. Lithium's effectiveness in suicide prevention has also been demonstrated. While antidepressants may treat depression, they often exacerbate symptoms of agitation, restlessness, irritability, and anger that can lead to impulsivity and aggression. Lithium, by contrast, has specific effects against suicide that are independent of mood stabilization. Substantial literature also exists to support the use of lithium in a broad spectrum of other neurological conditions including substance abuse, violent and aggressive behavior, ADHD, and cognitive decline.
    
The pharmacological mechanisms under which lithium operates have yet to be understood in totality, although many well-supported hypotheses exist. It appears that lithium functions in two central ways in the body's neurochemistry: repairing damaged neurons and stimulating neuronal growth. Proposed mechanisms for lithium's effect on balancing mood include the altering of dopamine, glutamate, and GABA levels in the synapses as well as modulation of secondary messenger pathways that effect neurotransmission, including the adenylyl cyclase system, cAMP signaling pathway, and phosphoinositide system. Accumulating evidence has shown that lithium's diverse neuroprotective actions involve direct changes in the expression of multiple genes.
    
It was once believed that genes were destiny. Scientists and clinicians held fast to the idea that a fixed genetic code was hardwired in humans at conception, and that mutations were a sure predictor of disease. However, it is now known that environmental factors have a profound influence on the ways in which genes are expressed. The study of epigenetics has revealed that lifestyle factors, including physical activity, learning, stress exposure, and pharmacological compounds, can essentially switch genes on or off. The mineral lithium is a powerful epigenetic factor. Key epigenetic mechanisms include histone modifications and changes in DNA methylation. Lithium works in both of these channels and has been shown to influence the expression of over 50 different genes. Working in these epigenetic pathways, lithium supports a wide range of neuroprotective and neurotrophic actions that literally change brain physiology.

Low-Dose Lithium

I believe that lithium is the most effective medication in psychiatry. Psychiatrists over the years have been hesitant to prescribe lithium because it is toxic at pharmaceutical doses. Concerns about side effects and toxicity are nonexistent when lithium is used as a nutritional, low-dose supplement. The untapped potential of low-dose lithium in psychiatry has implications for dramatically changing clinical practice with a safe, integrative strategy for the treatment of mental illness.
    
I have treated children as young as 4 years old and adults in their 70s with low-dose lithium. Here are a few examples of the hundreds of patients in whom this treatment has been successful. 
    
A 4-year-old boy, Peter, had severe ADHD. Even at this young age, he was shunned by other children, and his parents were asked to remove him from preschool. It was easy to observe his aggressive behaviors in my office. A trace mineral analysis from a hair sample revealed no detectable lithium. I prescribed 250 mcg of lithium in liquid form. Peter's annoying aggressiveness diminished. He became able to make friends, and eventually he began to participate cooperatively with other children in a new preschool.
    
Shawn at age 8 was often in trouble for bullying. Although he had been diagnosed with ADHD, stimulants had not been helpful. His trace mineral analysis showed no detectable lithium. On 2 mg of lithium orotate, he showed significant improvement, and he lost interest in bullying other children.
    
A 20-year-old patient, Amy, was diagnosed with bipolar disorder. She had been doing better on Depakote, although she continued to have anger outbursts and uncontrolled rages. Although she had once been on prescription lithium, she had experienced side effects that prevented ongoing use. I prescribed 10 mg of lithium for her in conjunction with the Depakote. Her condition improved so much that she was able to leave a therapeutic boarding school to return home. 
    
A middle-aged man named Brian made an appointment with me to talk about his problems with anger and irritability. I had no trouble imagining these problems, as I was unavoidably 15 minutes late in calling him to my office. He berated me for most of the session, and I later heard that he had been verbally abusive with my staff. Brian, I learned, had suffered from depression and was currently taking an antidepressant, but his irritability remained. His wife reported that his road rage escalated to such intensity that he would get out of the car and yell at other drivers. I added 10 mg of lithium to Brian's antidepressant treatment. Both he and his wife later reported that his simmering road rage subsided to nothing more than mild frustration.
    
The case of my patient Patricia was revealing by all of my assessment strategies: clinical history, family history, and trace mineral analysis. A 43-year-old therapist, she had been diagnosed at age 18 with depression and alcohol abuse. I learned from her story that her family of origin was deeply impaired by alcoholism. Patricia had been taking an antidepressant and had worked hard at maintaining her sobriety for 10 years. She came to me for enhanced support, as she complained that she was a "dry drunk," clinging to "white-knuckle sobriety." She felt chronically irritable. Trace mineral analysis revealed some level of lithium in her hair, but it was low. 
    
Six weeks after I prescribed 5 mg of lithium, Patricia came to my office in tears. She was partly joyful that she no longer felt a constant level of irritability, but she also realized with regret what it must have been like for her family to have tolerated her irritability and anger for such a long time.
    
In an effort to organize and disseminate the information of low-dose lithium, I have started to compile additional case studies and ongoing research efforts on the website www.lowdoselithium.org. 
    
In 1970, one research study analyzed levels of organically derived lithium in the water of 27 Texan counties and compared them to the incidence of admissions and readmissions for psychoses, neuroses, and personality disorders at local state mental hospitals. Data from a 2-year period were collected and analyzed. The authors noticed a marked trend: the higher the lithium content in the water supply, the lower the rate of psychiatric illness in that county. This association remained significant even after correcting for possible confounding variables such as population density and distance to the nearest state hospitals.
    
A follow-up study in the same Texan counties looked at similar variables over a longer 9-year span. Researchers came up with almost identical results: the incidences of suicide, homicide, and rape were significantly higher in counties where drinking water contained little or no lithium, versus those with levels ranging from 70 to 170 mcg/L. Unsure if these striking findings were somehow unique to that geographical region, other researchers have sought to replicate the study template in other areas throughout the globe. Lithium water studies have now been repeated internationally at sites in Austria, England, Greece, and Japan. Overall the collection has revealed a strong inverse correlation between aggressive crime and suicide and supplemental levels of lithium in the water supply.

Another interesting finding came from a study that looked at lithium levels in the hair of criminals. Trace mineral hair analysis is one of the most accurate methods for testing long-term mineral status and is therefore highly advantageous for determining where deficiencies are present. This study found that violent criminals had little to no stores of lithium when tested via hair mineral analysis, bringing forth the idea that perhaps lithium deficiency was contributing to oppositional and aggressive behaviors. 
    
The most fascinating research recently, however, has been on the use of lithium for Alzheimer's disease. Given its being the only cause of death in the top 10 in America that cannot be prevented, cured, or slowed, researchers are spending billions of dollars on Alzheimer's disease. There is a fast-growing community of researchers suggesting that lithium may provide significant benefits in the treatment and prevention of Alzheimer's.
    
Lithium has been shown to disrupt the key enzyme responsible for the development of amyloid plaques and neurofibrillary tangles associated with Alzheimer's disease. This enzyme is glycogen synthase kinase-3 (GSK-3), a serine/threonine protein kinase that is important in neural growth and development. Notably, specific levels of GSK-3 are required to carry out the synaptic remodeling that drives memory formation. 
    
In Alzheimer's disease, GSK-3 becomes hyperactive in the areas of the brain controlling memory and behavior, including the hippocampus and frontal cortex. This upregulation spurs GSK-3 to phosphorylate, or activate, amyloid-B and tau proteins in the neurons of these regions at an aberrantly high rate. Over time these proteins accumulate to create the signature plaques and neurofibrillary tangles that disrupt the brain tissue and result in symptoms of cognitive decline. Lithium works as a direct GSK-3 inhibitor to prevent this overexpression, halting inappropriate amyloid production and the hyperphosphorylation of tau proteins before they impair brain function.
    
In addition to protecting the brain from the development of plaques and tangles, lithium has been shown to repair existing damages brought about by Alzheimer's disease pathogenesis. Lithium ions, for example, encourage the synthesis and release of key neurotrophic factors such as brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3), which in turn stimulate the growth and repair of neurons. Patients on lithium have been found to have significantly higher gray matter volumes in the brain. One study has even directly demonstrated that damaged nerve cells exposed to lithium respond with increases in dendritic number and length. 
    
In a recent trial published in Current Alzheimer's Research, a nutritional dose of just 300 mcg of lithium was administered to Alzheimer's patients for 15 months. When compared with the control, those on low-dose lithium showed significant improvements in cognitive markers after just 3 months of treatment. Furthermore, these protective effects appeared to strengthen as the study proceeded, with many of the lithium-treated individuals showing marked cognitive improvements by the end of the trial. These results suggest that lithium could be a viable treatment for Alzheimer's disease when used at low doses over the long term.
    
Dr. Nassir Ghaemi, one of the more notable and respected advocates of lithium use in the medical community, recently published a review in 2014 in Australian and New Zealand Journal of Psychiatry summarizing the benefits of low-dose lithium therapy. Ghaemi and his colleagues performed a systematic review of 24 clinical, epidemiological, and biological reports that assessed standard or low-dose lithium for dementia along with other behavioral or medical benefits. Five of the seven epidemiological studies established a correlation with standard-dose lithium therapy and low dementia rates, while four other randomized clinical trials demonstrated that low-dose lithium yielded more benefit for patients with Alzheimer's dementia versus placebo. Based on these findings, Ghaemi stressed that "lithium is, by far, the most proven drug to keep neurons alive, in animals and in humans, consistently and with many replicated studies."

The Future of Lithium

Recognizing that nutrition is key to brain health is a fundamental premise of integrative medicine. Instead of focusing on just one type of intervention, integrative medicine tries to address all factors that may contribute to a mental disorder – bringing together nutritional supplements, medicines, psychotherapy, and lifestyle changes.
    
Lithium must be recognized as a critical component of nutritional assessments. Lithium is an underused nutritional supplement. The diverse neuroprotective mechanisms are truly remarkable. The scientific literature has shown that lithium modulates GSK-3, enhances the release of neurotrophic factors such as BDNF, and promotes epigenetic changes that resets the trajectory of mental illness. Lithium is powerful, reliable, cost effective, and, at low doses, completely safe. 
    
With low-dose lithium, we have a safe nutritional supplement that is effective in treating a wide range of disabling symptoms of mental illness. Perhaps in the future, patients like Jamie Lowe, the author of the New York Times article, will not be forced to make a decision between mental and physical health. The compelling and growing scientific literature on the benefits of low-dose lithium therapy combined with over 25 years of clinical practice have convinced me that with low-dose lithium, it is entirely possible to have both.


References

Bech P. The full story of lithium. Nord J Psychiatry. 2007;61(46):35–39. 
Cade JFJ. Lithium salts in the treatment of psychotic excitement. Med J Aust. 1949;2.
Diniz BS, Machado-Vieira RM, Forlenza OV. Lithium and neuroprotectin: translational evidence and implications for the treatment of neuropsychiatric disorders. Neuropsychiatr Dis Treat.2013;9:493–500.
Farah R et al. Lithium's gene expression profile, a cDNA microarray study. Cell Mol Neurobiol. 2013;33:411–420. 
Mauer S, Vergne D, Ghaemi NS. Standard and trace-dose lithium: a systematic review of dementia prevention and other behavioral benefits. Aust N Z J Psychiatry. 2014;48(9):809–818. 
Nunes MA, Viel TA, Buck HS. Microdose lithium treatment stabilized cognitive impairment in patients with Alzheimer's disease. Curr Alzheimer Res. 2013;10(1):104–107.
Shorter E. The history of lithium therapy. Bipolar Disord. 2009;11(2):4–9.
Schrauzer GN. Lithium: occurrence dietary intakes, nutritional essentiality. J Am Coll Nutr.2002;21(2):14–21.
Schrauzer GN, de Vroey E. Effects of nutritional lithium supplementation on mood. Biol Trace Elem Res.1994;40:89–101.
Schrauzer GN, Shrestha KP. Lithium in drinking water and the incidences of crimes, suicides and arrests related to drug addictions. Biol Trace Elem Res. 1990;25:105–113.
Strobasch AD, Jefferson JW. The checkered history of lithium in medicine. Pharm Hist.1980;22(2):72–76.
Young AH, Hammond JM. Lithium in mood disorders: increasing evidence base, declining use? Br J Psychiatry 2007;191:474–476.
Young W. Review of lithium effects on brain and blood. Cell Transplant. 2009;18:951–975.

James M. Greenblatt, MD, currently serves as the chief medical officer and vice president of Medical Services at Walden Behavioral Care in Waltham, Massachusetts. He is assistant clinical professor of psychiatry at Tufts University School of Medicine. An acknowledged integrative medicine expert, Dr. Greenblatt has lectured throughout the US on the scientific evidence for nutritional interventions in psychiatry and mental illness. Dr. Greenblatt is on the scientific advisory board and consultant for Pure Encapsulations. He maintains an integrative psychiatric practice in the Boston area.

Kayla Grossmann, RN, works as a nurse advocate and freelance writer specializing in integrative health research and practice. She supports several large organizations in the field by contributing to their ongoing educational initiatives and clinical programming.

Find out more about their upcoming book and work on www.lowdoselithium.com.

Magnesium: The Missing Link in Mental Health?

by James Greenblatt, MD

Chief Medical Officer at Walden Behavioral Care in Waltham, MD
Assistant Clinical Professor of Psychiatry at Tufts University School of Medicine and Dartmouth College Geisel School of Medicine

Magnesium is a cofactor in more than 325 enzymatic reactions—in DNA and neurotransmitters; in the bones, heart and brain; in every cell of the body. Unfortunately, a deficiency of this crucial mineral is the most common nutritional deficiency I see in my practice as an integrative psychiatrist. Fortunately, supplementation with magnesium is the most impactful integrative treatment I use, particularly in depression and attention deficit hyperactivity disorder (ADHD).

Why is magnesium deficiency so common, and why is restoring the mineral so essential to mental and emotional well-being and behavioral balance? The rest of this article addresses those two questions, and presents aspects of my therapeutic approach.

Magnesium Deficiency

 The population is deficient in magnesium—found abundantly in whole grains, beans and legumes, nuts and seeds, and leafy greens, as well as cocoa and molasses—for several reasons.

Soil depletion. Intensive agricultural practices rob the soil of magnesium and don’t replace it. As a result, many core food crops—such as whole grains—are low in magnesium. A recent paper in Crop Journal put it this way: Magnesium’s “importance as a macronutrient ion has been overlooked in recent decades by botanists and agriculturists, who did not regard Mg deficiency in plants as a severe health problem. However, recent studies have shown, surprisingly, that Mg contents in historical cereal seeds have markedly declined over time, and two thirds of people surveyed in developed countries received less than their minimum daily Mg requirement.” [1]  

Food processing. Magnesium is stripped from foods during food processing. For example, refined grains—without magnesium-rich germ and bran—have only 16% of the magnesium of whole grains. [2]

Stress. Physical and emotional stress—a constant reality in our 24/7 society—drain the body of magnesium. In fact, studies show inverse relationships between serum cortisol and magnesium—the higher the magnesium, the lower the cortisol. Stress robs the body of magnesium—but the body must have magnesium to respond effectively to stress.

Other factors. Many medications—such as medications for ADHD—deplete magnesium. So does the intake of alcohol, caffeine and soft drinks.

The result: In 1900, the average intake of magnesium was 475 to 500 mg daily. Today, it’s 175 to 225 mg daily. Which means that only one-third of adult Americans get the daily RDA for magnesium—320 mg for women, and 420 mg for men. (And many researchers consider the RDA itself inadequate.)  And that magnesium deficit causes deficits in health. Magnesium deficiency has been cited as contributing to atherosclerosis, hypertension, type 2 diabetes, obesity, osteoporosis and certain types of cancer. [4] But detecting that deficiency in laboratory testing is difficult, because most magnesium in the body is stored in the skeletal and other tissues. Only 1% is in the blood, so plasma levels are not a reliable indicator. That means a “normal” magnesium blood level may exist despite a serious magnesium deficit. An effective therapeutic strategy: Assume a deficit is present, and prescribe the mineral along with other appropriate medical and natural treatments. That’s particularly true if the patient has symptoms such as anxiety, irritability, insomnia and constipation, all of which indicate a magnesium deficiency.

The Mind Mineral

Some of the highest levels of magnesium in the body are found in the central nervous system, with studies dating back to the 1920s showing how crucial magnesium is for a balanced brain…

It’s known, for example, that magnesium interacts with GABA receptors, supporting the calming actions of this neurotransmitter. Magnesium also keeps glutamate—an excitatory neurotransmitter—within healthy limits. Patients with higher magnesium levels also have healthy amounts of serotonin in the cerebrospinal fluid. And the synthesis of dopamine requires magnesium.

In summary, the body needs magnesium to create neurotransmitters (biosynthesis) and for those neurotransmitters to actually transmit. Magnesium also acts at both the pituitary and adrenal levels. In the pituitary gland, it modulates the release of ACTH, a hormone that travels to the adrenal glands, stimulating cortisol release. In the adrenal gland, it maintains a healthy response to ACTH, keeping cortisol release within a normal range. As a result, magnesium is a must for maintaining the homeostasis of the HPA axis. Given all these key mechanisms of action, it’s not surprising that a lack of the mineral can produce psychiatric and other types of problems. The patient may have: Difficulty with memory and concentration. Depression, apathy and fatigue. Emotional lability. Irritability, nervousness and anxiety. Insomnia. Migraine headaches. Constipation. PMS. Dysmenorrhea. Fibromyalgia. Autism. ADHD. Fortunately, studies show that magnesium repletion—restoring normal levels of the mineral—produces positive changes in mood and cognition, healthy eating behavior, healthy stress responses, better quality of sleep, and better efficacy of other modalities, such as medications. Let’s look at two areas in which magnesium supplementation is particularly effective: Depression and ADHD.

Depression

A cross-sectional, population-based data set—the National Health and Nutrition Examination Survey—was used to explore the relationship of magnesium intake and depression in nearly 9,000 US adults. Researchers found significant association between very low magnesium intake and depression, especially in younger adults. [5] And in a recent meta-analysis of 11 studies on magnesium and depression, people with the lowest intake of magnesium were 81% more likely to be depressed than those with the highest intake. [6] In a clinical study of 23 senior citizens with depression, low blood levels of magnesium and type 2 diabetes, magnesium was compared to the standard antidepressant medication imipramine (Tofranil)—one group received 450 mg of magnesium daily and one group received 50 mg of imipramine. After 12 weeks, depression ratings were equally improved in both groups. [7] In my practice, I nearly always prescribe magnesium to a patient with diagnosed depression. You can read more about the integrative approach to depression in Integrative Therapies for Depression: Redefining Models for AssessmentTreatment and Prevention (CRC Press), which I co-edited, and in Breakthrough Depression Solution: Mastering Your Mood with Nutrition, Diet & Supplementation (Sunrise River Press, 2nd Edition).

Attention Deficit Hyperactivity Disorder

Magnesium deficiency afflicts 90% of all people with ADHD and triggers symptoms like restlessness, poor focus, irritability, sleep problems, and anxiety. These symptoms can lessen or vanish one month after supplementation starts. Magne­sium can also prevent or reverse ADHD drug side effects. That’s why all of my ADHD patients get a prescription for magnesium. For adolescents, I typically prescribe 200 mg, twice daily. For children 10 to 12, 100 mg, twice daily. For children 6 to 9, 50 mg, twice daily. Typically, I recommend magnesium glycinate, using a powdered product. I describe my entire approach to magnesium and ADHD (and to the disorder’s overall integrative treatment) in my book Finally Focused: The Breakthrough Natural Treatment Plan for ADHD That Restores AttentionMinimizes Hyperactivity, and Helps Eliminate Drug Side Effects. (Forthcoming from Harmony Books in May 2017)

Dosage and Form

I have found that 125 to 300 mg of magnesium glycinate at meals and a bedtime (four times daily) produces clinically significant benefits in mood. (This form of magnesium is gentle on the digestive tract.) 200 to 300 mg of magnesium glycinate or citrate before bed supports sleep onset and duration through the night. You can also find magnesium in powder or liquid form, which are effective alternatives to capsules, particularly for children with ADHD. Ways to increase the bioavailability of magnesium include: Supplementing with vitamin D3, which increases cellular uptake of the mineral. Vitamin B6 also helps magnesium accumulate in cells. Taking the mineral in divided doses instead of a single daily dose. Taking it with carbohydrates, with improves absorption from the intestine. And taking an organic form, such as glycinate or citrate, which improves absorption by protecting the mineral from antagonists in the digestive tract. Avoid giving magnesium in enteric-coated capsules, which decreases absorption in the intestine.

Magnesium oxide is poorly absorbed and tends to cause loose stools. Magnesium-l-threonate has been shown to readily cross the blood-brain barrier, and animal studies show that it supports learning ability, short and long-term memory and brain function, I don’t typically prescribe it, however, because of its higher cost, and the clinical effectiveness of other forms. The therapeutic response to magnesium typically takes several weeks, as levels gradually increase in the body.

CITATIONS

[1] Guo W., et al. Magnesium deficiency in plants: An urgent problem. The Crop Journal, Volume 4, Issue 2, April 2016, Pages 83-91.

[2] http://www.ancient-minerals.com/magnesium-sources/dietary/

[3] https://www.washingtonpost.com/national/health-science/magnesium-is-essential-to-your-health-but-many-people-dont-get-enough-of-it/2017/06/09/77bc35b4-2515-11e7-bb9d-8cd6118e1409_story.html?noredirect=on&utm_term=.b92d507bf92a

[4] Volpe, SL. Magnesium in Disease Prevention and Overall Health. Advances in Nutrition, 2013 May; 4(3): 378S-383S.

[5] Tarleton EK, at al. Magnesium Intake in Depression in Adults. Journal of the American Board of Family Medicine, 2015 Mar-Apr;28(2):249-56.

[6] Li B, et al. Dietary magnesium and calcium intake and risk of depression in the general population: A meta-analysis. Australian and New Zealand Journal of Psychiatry, 2016 Nov 1. [Epub ahead of print].

[7] Barragan-Rodriquez L, et al. Efficacy and safety or oral magnesium supplementation in the treatment of depression in the elderly with type 2 diabetes: a randomized, equivalent trial. Magnesium Research, 2008 Dec;21(4):218-23.

Examining the Gut-Brain Connection and Its Implications for Trichotillomania Treatment

James Greenblatt, MD

Trichotillomania (TTM) is an impulsive disorder that causes people to repeatedly pull out their hair, most often from the scalp. It affects about 1-2% of adults and adolescents, but it is ten times more prevalent in women than in men (APA, 2013). The name is Greek in origin: thrix (hair), tillein (to pull), and mania (madness). The first allusion to TTM may have come from the Greek philosopher Epictetus in 101 AD: “Indeed I think that the men who pluck out their hairs do what they do without knowing what they do…Much from his head he tore his rooted hair. And what does he say himself? 'I am perplexed,' he says, 'and disturbed I am,' and 'my heart out of my bosom is leaping.'" (Epictetus, 1981). The first medical case was described by French dermatologist Francois Henri Hallopeau in 1889, who described a young man who pulled out his hair in tufts (Parakh & Srivastava, 2010).

The American Psychiatric Association first recognized TTM as a mental disorder in 1987. The DSM V classifies TTM as an obsessive-compulsive disorder, a change from the DSM IV where is was classified as an impulsive-control disorder (APA, 2013). The cause is complex and unclear. Those with TTM often suffer from other psychiatric conditions such as major depression, generalized anxiety disorder, OCD, eating disorders, substance abuse, and excoriation (skin-picking) disorder (Parakh & Srivastava, 2010).

The last 20 years have begun to shed some light on the disorder with an increase in clinical and research attention; however, there is yet to be a consensus on the best treatment. Traditional treatments primarily involve cognitive-behavioral therapy including habit reversal therapy. Cognitive-behavioral therapy identifies factors triggering hair pulling behavior and then teaches skills to interrupt the behavior. This includes keeping records of hair pulling, being aware of emotional states or environmental cues causing the behavior, or bandaging fingers to interfere with hair pulling. Habit reversal therapy is currently the most effectively used treatment, although treatment varies on an individual basis and relapse is common. Medications used to treat TTM include selective serotonin reuptake inhibitors (SSRIs), olanzapine, clomipramine, fluoxetine, and paroxetine. SSRIs are currently the most commonly used treatment in children and adults (Bruce et al., 2005).

Unfortunately, the effectiveness of these traditional treatments is mixed. One meta-analysis concluded that there was no evidence to demonstrate that SSRIs are more efficacious than placebo in the treatment of trichotillomania (Bloch et al., 2007). According to a Trichotillomania Impact Project survey, treatments for TTM have only been successful with 15% of adult patients and 17% of pediatric patients (Woods et al., 2006). Due to the lack of effective treatment options for TTM, individuals struggling with TTM are seeking alternative treatments that may be more successful than traditional forms of treatment, such as probiotics, N-acetylcysteine, and inositol.

Probiotics are beneficial bacteria that are introduced into the gastrointestinal tract. Interestingly, gut bacteria are able to synthesize the same neurotransmitters that are found in the brain. These gut neurotransmitters have the same structure and are produced via the same biosynthetic pathway as those in the brain. Gut bacteria are able to communicate with the brain through the vagus nerve, a phenomenon known as the “gut-brain connection.” Researchers have found that probiotics can improve many aspects of psychological health including depression and anxiety by modifying the gut microbiome. Probiotics can also directly modulate the immune system (Lyte, 2011).

Success stories attest to the ability of probiotics to offer relief to individuals suffering from TTM. A year after my article “Gut feelings: the future of psychiatry may be inside your stomach” was published on The Verge, I was contacted via email by a gentleman who shared his incredible story on how he was able to cure himself from trichotillomania by using probiotics after reading the article. Here is his story:

“I am a middle aged Caucasian male, and my first history of chronic hair pulling was when I had a very brief episode when I was in the 7th grade. First off, let me explain what I tried to do in the past, all unsuccessfully, to find a solution. I tried pure willpower. I tried discussing my hair pulling with my family doctor. I went to a psychiatrist, one of the most talented psychiatrists in the field, and he told me that there was nothing that psychiatry could do for me. I just happened to stumble onto an article on the web about a psychiatrist that was successfully treating some of his patients with various Obsessive Compulsive disorder symptoms with Probiotics! I started taking two capsules of 30 billion CFU capsules a day on the day after Thanksgiving, 2013. In the last week of January of 2014 I all of a sudden realized, one day, “Hey, wait a minute, I have not pulled my hair for the past 2 weeks now”. It seems I had stopped hair pulling in mid-January and didn’t even notice it until two weeks had gone by. I was hopeful, but skeptical at that point. Over the past 15 years, I have never, ever, had more than a 1 day period of time that I did not pull out my own hair. I continued taking the probiotics every day. As of the day I am writing this, today, July 17, 2014, I have not pulled even one hair since mid-January. Not only have I been symptom free, but I never had to apply any will power or focus on stopping the hair pulling to help me stop. What happened is that the urges did not need to be fought off, they simply dissipated by themselves and have completely disappeared, all by themselves. I did no counseling sessions, no coaching sessions, no group therapy, no psychiatric medications, no psychological treatments of any kind, nothing except the probiotics.”

You can read his full story on https://howicuredmyhairpulling.wordpress.com

N-acetylcysteine (NAC) also shows promise for reducing compulsive behavior. NAC is an amino acid that is converted in the body to a powerful antioxidant known as glutathione. In a double-blind trial, 50 adults with trichotillomania were randomized to NAC (1,200-2,400 mg/d) or placebo for 12 weeks. Those receiving NAC significantly improved on measures of urges to pull hair, actual amount of pulling, perceived control over the behavior, and distress associated with hair pulling. Of those taking NAC, 56% were “much” or “very much” improved compared with 16% of those taking placebo (Grant et al., 2009).

There is also emerging evidence for inositol as treatment for TTM. Inositol is a sugar produced by the human body from glucose. The sugar is found in many foods, particularly fruits such as cantaloupe and oranges. Inositol is a signaling molecule involved in many important functions such as nerve guidance and the breakdown of fats. In the past, inositol has been used effectively for depression, anxiety, and OCD. Two case studies have been documented of young women with TTM who befitted from 18 grams per day of inositol (Seedat et al., 2001). Inositol is thought to help regulate serotonin levels, which is particularly relevant for disorders including TTM, OCD, depression, and anxiety that may be caused by low levels of serotonin.

Indeed, disruptions in the gastrointestinal tract or gut microbiota can manifest as physiological and psychological symptoms. Fortunately, several animal studies have found that the introduction of probiotics were effective at modulating the gut microbiota. While the complex connection between the gut and brain continue to be examined, the available research suggests that probiotics may be a promising intervention for several illnesses including depression, anxiety, and compulsive disorders. 

REFERENCES

American Psychiatric Association (APA). (2013). Diagnostic and statistical manual of mental disorders (5th ed.). Arlington, VA: American Psychiatric Publishing.

Bloch, M. H., Landeros-Weisenberger, A., Dombrowski, P., Kelmendi, B., Wegner, R., Nudel, J., & ... Coric, V. (2007). Review: Systematic Review: Pharmacological and Behavioral Treatment for Trichotillomania. Biological Psychiatry, 62(Bipolar Disorder and OCD: Circuitry of Impulsive and Compulsive Behaviors), 839-846.

Bruce, T. O., Barwick, L. W., & Wright, H. H. (2005). Diagnosis and management of Trichotillomania in children and adolescents. Pediatric Drugs, (6), 365.

Epictetus, Long, G., & Epictetus. (1891). The discourses of Epictetus ; with the Encheiridion and fragments / reprinted from the translation of George Long. London : G. Bell and Sons, 1891 ([London] : Chiswick Press).

Grant, J., Odlaug, B., & Suck, W. (2009). N-acetylcysteine, a glutamate modulator, in the treatment of trichotillomania: A double-blind, placebo-controlled study. Archives Of General Psychiatry, 66(7), 756-763.

Lyte, M. (2011). Probiotics function mechanistically as delivery vehicles for neuroactive compounds: Microbial endocrinology in the design and use of probiotics. Bioessays, 33(8), 574-581.

Parakh, P., & Srivastava, M. (2010). The Many Faces of Trichotillomania. International Journal of Trichology, 2(1), 50–52.

Seedat, S., Stein, D. J., & Harvey, B. H. (2001). Inositol in the treatment of trichotillomania and compulsive skin picking. The Journal Of Clinical Psychiatry, 62(1), 60-61.

Woods, D. W., Flessner, C. A., Franklin, M. E., Keuthen, N. J., Goodwin, R. D., Stein, D. J., & Walther, M. R. (2006). The trichotillomania impact project (TIP): Exploring phenomenology, functional impairment, and treatment utilization. Journal Of Clinical Psychiatry, 67(12), 1877-1888.

The Future of Depression Treatment (Audio Interview)

JAMES GREENBLATT, MD

Guest: Dr. James Greenblatt
Presenter: Neal Howard
Guest Bio: James M. Greenblatt, MD, is a pioneer in the field of integrative medicine and one of the founders of Integrative Medicine for Mental Health (IMMH). He currently serves as the chief medical officer and vice president of medical services at Walden Behavioral Care in Waltham, Massachusetts. Dr. Greenblatt is also an assistant clinical professor in the Department of Psychiatry at Tufts University School of Medicine in Boston.

Segment overview: Dr. James Greenblatt, MD, author of “Breakthrough Depression Solution: Mastering Your Mood with Nutrition, Diet & Supplementation”, talks about the treatment of depression in the future and how it is not a one-size-fits-all prescription.

Originally published to Health Professional Radio

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.


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.

Lithium: The Cinderella Story about a Mineral That May Prevent Alzheimer’s Disease

James Greenblatt, MD and Kayla Grossman, RN

*Originally published in the December 2015 issue of The Neuropsychotherapist

Every four seconds, someone in the world develops dementia. Worldwide, an estimated 35.6 million people already live with a form of this neurodegenerative disorder, and these numbers are on a staggering rise. The World Health Organization has projected that the number of cases of dementia will double by 2030 (65.7 million) and triple by the year 2050 (115.4 million). Already in America the most common type of dementia, Alzheimer’s disease, is the sixth leading cause of death; one in three seniors passes with this type of crippling memory loss. (WHO, 2015)

Progressive memory loss that interferes with activities of daily living is not a normal part of aging. In fact, research is showing that cognitive decline is the result of pathophysiological processes deep within the brain beginning many years, even decades, before dementia symptoms start.

This knowledge is frightening. It brings attention to the pervasive and silent nature of these diseases. Neurodegenerative disorders have become an international public health issue with devastating medical, social and economic consequences. And yet, from the perspective of conventional medicine, relatively little is known about how to treat or stop them.

In the midst of a harrowing race to find answers, one unassuming prevention strategy has shown promise above the rest. This remedy is none other than the simple, brain-protecting mineral: lithium.

Understanding Alzheimer’s Disease
Chances are you’ve heard of Alzheimer’s disease before,or may even know someone who has suffered from it. Alzheimer’s disease is a tragic neurological malady characterized by a progressive and irreparable shrinking of brain tissue. The result is a devastating decline in memory, social abilities and communication skills in sufferers leading, eventually, to death.

Less than 5 percent of the time, Alzheimer’s disease results from a specific genetic combination that essentially guarantees a person will develop the disease. More commonly it is the result of a complex combination of subtle genetic, lifestyle and environmental factors that affect the brain over a lifetime. Scientists believe that Alzheimer’s disease is not an acute condition, but rather the result of numerous damages that occur over the years. This slow, cumulative patterning helps to explain why most patients with Alzheimer’s disease don’t present with symptoms until over the age of 65.

Pathologically, Alzheimer’s disease is the result of two trademark injuries or lesions that occur at the cellular level: plaques and tangles. Plaques are formed by deposits of small protein fragments called amyloid-B or beta-amyloid peptides. Clumps of these proteins block the synapses or spaces between brain cells or neurons. With the synapses barricaded, normal cell-to-cell signaling cannot occur and communication is essentially stopped in certain regions of the brain. Meanwhile, other lesions, called neurofibrillary tangles, develop within the neurons themselves. These tangles result from a disruption in the production of a different type of protein, called tau. Normally, tau protein filaments help to circulate nutrients and other essential supplies throughout the cell. In Alzheimer’s disease however, the strands destabilize, becoming twisted or “tangled”. Without this system to circulate vital compounds, neurons “starve” or die. The physiological processes required for memory and learning are halted, and symptoms begin to arise.

There is now evidence to show that these damaging beta-amyloid plaques and neurofibrillary tangles may actually be a relatively common malformation in the aging human brain. New research is revealing that plaques can appear a full 30-40 years before symptoms of cognitive decline even begin to show. (Langbaum et al., 2013) One recent study published in the Journal of the American Medical Association churned up the following statistics: 10% percent of healthy 50-year-olds have amyloid deposits. This figure swells to 33% by age 80, and 44% at age 90. (Visser et al., 2015). Individuals with a mental illness, specifically patients with depression or bipolar disorder, are at an even greater risk for developing these dementia-precursors in the brain. (DaSilva et al., 2013)

Nutrition and Brain Health
Currently there are no widely accepted preventative, or even ameliorative, treatments for most dementias including Alzheimer’s disease. A swarm of clinical trials have been launched in recent years, all with the goal of finding effective pharmaceutical interventions to stop or slow the progression of neurodegenerative disorders like Alzheimer’s disease. However between the years 2002 and 2012, 99.6% of drugs studies aimed at preventing, curing or improving Alzheimer’s symptoms were either halted or discontinued. (Devlin, 2013) Most of the tested drugs were making patients sicker, not better, and came with appalling side effects.

With pharmaceutical approaches failing, many clinicians and researchers are turning to nutrition to find their answers. Accumulating study results show that nutrition has profound effects on brain health. The brain functions at a high metabolic rate and uses a substantial portion of total nutrient intake. It relies on amino acids, fats, vitamins, minerals, and trace elements. These influence both brain structure and function. Nutrition also contributes to neuron plasticity and repair, key functions for mental health and well-being over the long term.

A collaborative research project funded by the National Institute on Aging recently found that individuals on a whole foods diet, rich in items like berries, leafy greens and fish, are at less of a risk for Alzheimer’s disease. (RUMC, 2015) Essential fatty acids such as omega-3s are also being studied at several large universities for their role in supporting brain health. Other experts have called Alzheimer’s disease “type 3 diabetes,” pointing to excess sugar intake as a major contributor to the disorder. The overlap between nutrition and cognitive function is becoming more widely accepted in the world of neurology.

Lithium: The Unlikely Treatment
One mineral that has shown great promise in the treatment of Alzheimer’s disease is the mineral lithium, a nutrient with established benefits for the treatment of mental health disorders.

Lithium salts have been used for centuries as a popular health tonic. Over the course of history this simple mineral has been applied to heal ailments as wide-ranging as asthma, gout, and migraines. Lithium springs were once sought-after health destinations, visited by authors, political figures and celebrities. Throughout the 19th and into the 20th century, lithium was used as a mineral supplement to fortify a variety of foods and beverages. The Sears, Roebuck & Company Catalogue of 1908 advertised Schieffelin’s Effervescent Lithia Tablets for a variety of afflictions. By 1907, The Merck Index listed 43 different medicinal preparations containing lithium. In 1929, a soft drink inventor named Charles Leiper Grigg even created a new lithiated beverage he called Bib-Label Lithiated Lemon-Lime Soda, now known as “7-Up.” The beverage contained lithium citrate until 1950, and was originally known and marketed for its potential to cure hang-overs after a night of drinking alcohol, and to lift mood.

Today lithium is still found naturally in food and water. The U.S. Environmental Protection Agency has estimated that the daily lithium intake of an average adult ranges from about 0.65 mg to 3 mg. Grains and vegetables serve as the primary sources of lithium in a standard diet, with animal byproducts like egg and milk providing the rest. Lithium has even been officially added to the World Health Organization’s list of nutritionally essential trace elements alongside zinc, iodine and others. 

In modern medicine, lithium is most widely acknowledged for its ability to encourage mood stability in patients with affective disorders. With years of research and clinical use to back it, a substantial body of evidence now exists to show that high-dose lithium restores brain and nervous system function, right down to the molecular level. This incredible mineral is now being considered for the treatment of cognitive decline.

Scientists first became interested in the use of lithium for treating neurodegenerative disorders when they observed that bipolar patients using lithium therapy seemed to have lower rates of cognitive decline than peers on other medications. In an attempt to figure out the legitimacy of this observation, one study compared the rates of Alzheimer's disease in 66 elderly patients with bipolar disorder and chronic lithium therapy, with the occurrence in 48 similar patients who were not prescribed the mineral. Findings in favor of lithium were staggering: patients receiving continuous lithium showed a decreased prevalence of Alzheimer’s disease (5%) as compared with those in the non-lithium group (33%). (Nunes et al., 2007) Two further studies in Denmark confirmed this phenomenon using different study designs, but achieving strikingly similar results. In this study series, investigators surveyed the records of over 21,000 patients who had received lithium treatment, and found that therapy was associated with decreased levels of both dementia and Alzheimer’s. (Kessing et al., 2008, 2010)

Unfortunately, the first clinical trials testing lithium with dementia patients proved disappointing. Researchers attempted to fit lithium into the same diagnostic treatment framework used by drug companies in the beginning: testing the therapy on patients who already had fully developed Alzheimer’s. At this point, the damages to the brain were simply too great to turn around.

One small, open-label study looked at low-dose lithium use in 22 Alzheimer’s disease patients over the course of one year. (MacDonald et al., 2008) While researchers concluded that prescription lithium salts were relatively safe in this population, there were no observed cognitive benefits. The small baseline sample size coupled with a high discontinuation rate, may have been to blame for these discouraging results. It may also have been too late for lithium to make a difference in these advanced stages of illness.

Another multi-center, single-blind study looked at the use of lithium sulfate in participants with mild Alzheimer’s disease over a 10 week period. (Hampel et al., 2009) They too failed to find significant effects of lithium treatment on cognitive performance or related biomarkers. One major issue with this trial however, was the length of observation. It likely takes months, not weeks, to see substantial cognitive shifts in patients.

A group led by Forlenza et al (2011), sought to correct for these initial design flaws. Focus was shifted away from the post-diagnosis period and settled on prevention. This unique study attempted to determine whether long-term lithium treatment could stop Alzheimer’s disease from occurring in high risk individuals. Forty-five participants with mild cognitive impairment (MCI), a precursor to Alzheimer’s, were randomized to receive lithium or a placebo. Over the 12-month trial, lithium dosages were kept at sub-therapeutic levels (150mg to 600mg daily) to minimize potential side effects. At the conclusion of the study, researchers discovered that those in the lithium group had a decreased presence of destructive tau proteins when compared to pre-study levels. This finding came in stark contrast to the the tau levels of the placebo group, which had increased steadily over the course of the study. What’s more, the lithium group showed improved performance on multiple cognitive scales. Overall tolerability of lithium was deemed good as patients reported limited side effects and the adherence rate to treatment was an impressive 91%. Researchers concluded that lithium had a significant disease-modifying impact on preventing dementia and Alzheimer’s disease when initiated early on in the disease progression.

The Promise of Low-Dose Lithium
Additional testing has found that lithium can be effective when used at low-doses or supplemental levels, similar to those found naturally in water and foods. Studies are beginning to show that the benefits of pharmaceutical lithium (used at an average of 600-1200 mg daily) can be achieved with much smaller and safer doses (between 1-20 mg). When lithium is used at these low or nutritional doses, the risks of side effects plummet.

Evidence pointing to the usefulness of low-dose lithium has come primarily from epidemiological studies conducted by geology specialists and other professionals. Eleven different studies have looked at lithium levels in the drinking water from various regions throughout the globe. Two dozen counties in Texas, the 100 largest American cities and 99 districts in Austria have been considered, alongside other locations in Greece and Japan.  (Dawson, 1970; Schrauzer & Shrestha, 1990; Kapusta et al., 2011 Kabacs et a., 2011; Giotakos et al., 2015; Sugawara et al., 2013) Lithium levels in the water have been compared to rates of behavioral issues (including psychiatric admissions, suicide, homicide, crimes), medical illnesses and overall mortality in these areas. Collectively the studies have analyzed outcomes in well-over 10 million subjects. In 9 of the 11 studies, a positive association between high lithium levels and beneficial behavioral, legal and medical outcomes has been observed. In each of the negative studies, levels of lithium were likely too low to yield any significant health effects. (Mauer et al., 2014)

These studies have spurred interest in the clinical applications of low-dose lithium, although trials have been slow coming. Because lithium is a naturally occurring mineral and is not patentable (and therefore not profitable), little financial backing has been put towards the cause. In one highly-regarded study published in Alzheimer’s Research however, a scant 0.3 mg of lithium was administered once daily to Alzheimer’s patients for 15 months. (Nunes, 2013) Those receiving lithium demonstrated stable cognitive performance scores throughout the duration of the study, while those in the control group suffered progressive declines.  Moreover, three months into the study, the seemingly impossible happened: the lithium treatment cohort began showing increasing mini-mental status scores.

Additional, high-quality trials using low-dose lithium are essential, especially in the realm of dementia and cognitive decline.

Key Neuroprotective Mechanisms
There is now clean scientific evidence to suggest not only that lithium protects the brain, but also how it does so. Lithium ions (at both high and low concentrations) have been shown to modify key cellular cascades that increase neuronal viability and resilience. Most prominently, lithium disrupts the key enzyme responsible for the development of the amyloid plaques and neurofibrillary tangles associated with Alzheimer’s disease. This enzyme is called Glycogen Synthase Kinase-3 (GSK-3)—a serine/threonine protein kinase that normally plays a major role in neural growth and development. In the healthy brain, GSK-3 is very important; it helps to carry out the synaptic remodeling that drives memory formation.

In Alzheimer’s disease however, GSK-3 becomes hyperactive in the areas of the brain that control cognition and behavior, including the hippocampus and frontal cortex. When “revved-up” in this way, GSK-3 phosphorylates, or activates, amyloid-B and tau proteins within the neurons. Eventually, these proteins accumulate and create the signature plaques and neurofibrillary tangles that disrupt brain function and result in symptoms of cognitive decline. Lithium works as a direct GSK-3 inhibitor to prevent this over-expression, halting inappropriate amyloid production and the hyper-phosphoryation of tau proteins before they become problematic. (Hooper et al., 2008; Wada, 2009)

In addition to protecting the brain from the development of plaques and tangles, lithium has been shown to repair existing damages brought on by the Alzheimer’s disease pathogenesis. Lithium ions for example, encourage the synthesis and release of key neurotrophic factors such as Brain Derived Neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) which in turn stimulate the growth and repair of neurons. (Leyhe et al., 2009) Patients on lithium have been found to have significantly higher gray matter volumes in the brain, hinting that lithium has powerful stimulatory effects on neurogenesis. One study has even directly demonstrated that damaged nerve cells exposed to lithium respond with increases in dendritic number and length. (Dwidivi & Zhang, 2014)

Conclusion
Alzheimer’s and dementia have become modern health problems of epidemic proportions. Nonetheless, relatively few pharmacological solutions have been discovered for preventing, treating and reversing associated cognitive decline. As conventional treatment approaches falter, clinicians and researchers have been turning more and more to natural alternatives. It has become increasingly evident that nutrition is a key factor when it comes to brain health.

Evidence suggests that the mineral lithium in particular, may play a major role in shifting the pathophysiological cascade associated with dementia and Alzheimer’s disease. In clinical studies, long-term lithium therapy has been found to decrease the problematic plaques and tangles leading to symptoms of cognitive decline. This powerful mineral acts by inhibiting damaging enzymes and stimulating the release of protective neurotrophic factors in the brain.

Lithium ions have been found to operate efficiently at low doses mimicking those found in nutritional sources. At these sub-pharmaceutical levels, lithium has been shown to be a beneficial and safe neuroprotective therapy across age groups and with minimal side effects.

The safety profile of low-dose lithium is particularly attractive, as prevention strategies for dementia are most effective when started early and continued for long periods of time. The dangerous plaques and tangles involved in Alzheimer’s disease start up to 40 years before the appearance of symptoms. What’s more, 10% of healthy 50 year olds already have amyloid deposits developing in the brain tissues. Thus, for optimal effectiveness, steps to protect the brain must be taken at a much younger age than previously thought.

When started early, low-dose lithium may be the key intervention to prevent cognitive decline. But first, we must move past the stigma that surrounds it. As psychiatrist Ana Fels wrote in her recent article for The New York Times, “[o]ne could make a case that lithium is the Cinderella of psychotropic medications, neglected and ill used.” Lithium is the single most proven substance to keep neurons alive, and yet it continues to be viewed in the public mind as a dangerous and scary drug. Lithium is found readily in our environment, food, water and each and every cell in the human body. It is time we change the conversation around one of nature’s most effective and powerful neuroprotective remedies.


References

  1. Da Silva, J., et al. 2013. Affective disorders and risk of developing dementia: systematic review. Br J Psychiatry 202:177-186
  2. Dawson, E.P., Moore, T.D. & McGanity, W.J. 1970.  The mathematical relationship of drinking water lithium and rainfall on mental hospital admission. Dis Nerv Syst 31:1–10.
  3. Devlin, H. 2015. Scientists find first drug that appears to slow Alzheimer’s Disease. The Guardian. Retrieved from: http://www.theguardian.com/science/2015/jul/22/scientists-find-first-drug-slow-alzheimers-disease.
  4. Dwivedi, T. & Zhang, H. 2014. Lithium-induced neuroprotection is associated with epigenetic modification of specific BDNF gene promoter and altered apoptotic-regulatory proteins. Front Neurosci 8:1-8.
  5. Fels, A. 2014. Should we all take a bit of lithium? The New York Times. Retrieved from: http://www.nytimes.com/2014/09/14/opinion/sunday/should-we-all-take-a-bit-of-lithium.html
  6. Forlenza, O. V., et al. 2011. Disease-modifying properties of long-term lithium treatment for amnestic mild cognitive impairment: randomized controlled trial. Br J Psychiatry 198:351-365.
  7. Giotakos, O., et al. 2015.  Lithium in the public water supply and suicide mortality in Greece. Biol Trace Elem Res 156(1–3):376–379.
  8. Hampel, H., et al. 2009. Lithium trial in Alzheimer’s disease: a randomized, single-blind, placebo- controlled, multicenter 10-week study. J Clin Psychiatry 70 (6): 922-31.
  9. Hooper, C., Killick, R., Lovestone, S. 2008. The GSK3 hypothesis of Alzheimer’s Disease. J Neurochem 104, 1433-1439.
  10. Kapusta N.D., et al. 2011. Lithium in drinking water and suicide mortality. Br J Psychiatry.198(5):346–350.
  11. Kessing, L. V., et al. 2008. Lithium treatment and risk of dementia. Arch Gen Psychiatry 65(11):1331-1335.
  12. Kessing, L.V., Forman, J.L., & Andersen, P.K. 2010. Does lithium protect against dementia? Bipolar Disord 12(1): 87-94.
  13. Langbaum, J.B.S., et al. 2013. Ushering in the study and treatment of preclinical Alzheimer’s Disease. Nat Rev Neurol 9(7): 371-381.
  14. Leyhe, T., et al. 2009. Increase of BDNF serum concentration in lithium treated patients with early Alzheimer’s Disease. J Alzheimers Dis 16:649-656.
  15. Macdonald, A., et al. 2008. A feasibility and tolerability study of lithium in Alzheimer’s disease. Int J Geriatr Psychiatry 23 (7): 704-11.
  16. Mauer, S., Vergne, D.,  & Ghaemi, S. N. 2014. Standard and trace-dose lithium: A systematic review of dementia prevention and other behavioral benefits. Aust NZ J Psychiatry Retrieved from: http://anp.sagepub.com/content/early/2014/06/10/0004867414536932
  17. Nunes, M. A., Viel, T. A., Buck, H. S. 2013. Microdose lithium treatment stabilized cognitive impairment in patients with Alzheimer’s Disease. Curr Alzhiemer Res 10, 104-107.
  18. Nunes, P. V., Forlenza, O. V., Gattaz, W. F. 2007. Lithium and risk for Alzheimer’s disease in elderly patients with bipolar disorder. Br J Psychiatry 190:359-60.
  19. Rush University Medical Center. 2015. Diet may help prevent Alzheimer’s: MIND diet rich in vegetables, berries, whole grains, nuts. Retrieved from: https://www.rush.edu/news/diet-may-help-prevent-alzheimers
  20. Schruazer, G.N.., & Shrestha, K.P. 1990. Lithium in drinking water and the incidences of crimes, suicide and arrests related to drug addiction. Biol Trace Elem Res 25: 105-113.
  21. Sugawara, N., et al. 2013. Lithium in tap water and suicide mortality in Japan. Int J Environ Res Public Health. 10(11):6044–6048.
  22. Visser P.J., et al. 2015. Prevalence of cerebral amyloid pathology in persons without dementia. JAMA 313(19):1924-1938.
  23. Wada, A. 2009. Lithium and neurpsychiatric therapeutics: neuroplascticity via glycogen synthase kinase-3B, B-catenin and neurotrohpin cascades. J Pharmacol Sci 110, 14-28.
  24. World Health Organization. 2015. Facts and Figures: Dementia. Retrieved from: http://www.who.int/mediacentre/factsheets/fs362/en/.

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 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.

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.