Evidence continues to accumulate regarding the important role of vitamin D in brain development and immune regulation. As such vitamin D is considered a neurosteroid. The authors of a paper published recently in the journal Psychoneuroendocrinology state:

“There is now clear evidence that vitamin D is involved in brain development.“

The specific focus of their study is schizophrenia as a developmental disorder. This is of interest to all parents and clinicians because the same mechanisms may be involved for neurodevelopmental disorders on a lower end of the spectrum of intensity including problems of learning and behavior.

“The origins of schizophrenia are considered developmental. We hypothesised that developmental vitamin D (DVD) deficiency may be the plausible neurobiological explanation for several important epidemiological correlates of schizophrenia…”

The authors developed an animal model to study the effects of vitamin D deficiency on brain development that included removing vitamin D from the diet during gestation while being sure to maintain normal calcium levels. The effects were dramatic:

“The brains of offspring from DVD-deficient dams are characterised by (1) a mild distortion in brain shape, (2) increased lateral ventricle volumes, (3) reduced differentiation and (4) diminished expression of neurotrophic factors. As adults, the alterations in ventricular volume persist and alterations in brain gene and protein expression emerge. Adult DVD-deficient rats also display behavioural sensitivity to agents that induce psychosis (the NMDA antagonist MK-801) and have impairments in attentional processing.”

The summarize their findings by stating:

“Our conclusions from these data are that vitamin D is a plausible biological risk factor for neuropsychiatric disorders and that vitamin D acts as a neurosteroid with direct effects on brain development.“

The authors of a paper published in the FASEB Journal (The Journal of the Federation of American Societies for Experimental Biology) report their review of the scientific evidence for the link between vitamin D and brain dysfunction. The examination included:

“1) biological functions of vitamin D relevant to cognition and behavior; 2) studies in humans and rodents that directly examine effects of vitamin D inadequacy on cognition or behavior; and 3) immunomodulatory activity of vitamin D relative to the proinflammatory cytokine theory of cognitive/behavioral dysfunction.”

The data over a wide range of topics was mixed, but the overall weight of evidence significant:

“We conclude there is ample biological evidence to suggest an important role for vitamin D in brain development and function…While mechanistic and biological evidence strongly suggests that calcitriol is involved in brain development and critical brain functions, it has proved more difficult experimentally to demonstrate obvious effects of vitamin D inadequacy on cognitive or behavioral endpoints…Despite residual uncertainty, we believe the evidence overall suggests that supplementation to ensure adequacy is prudent…”

Consider also a paper published a few months ago in Acta Neurologica Scandinavica that further examines the role of vitamin D in the central nervous system:

“Epidemiological and experimental evidence suggest that vitamin D deficiency is a risk factor for multiple sclerosis and other autoimmune diseases…Hypovitaminosis D is also associated with several other neurological diseases that is less likely mediated by dysregulated immune responses, including Parkinson’s disease and Alzheimer’s disease, schizophrenia and affective disorders, suggesting a more diverse role for vitamin D in the maintenance of brain health.”

Moreover…

“…both the vitamin D receptor and the enzymes necessary to synthesize bioactive 1,25-dihydroxyvitamin D are expressed in the brain, and hypovitaminosis D is associated with abnormal development and function of the brain.”

They offer insight into why studying the effects of vitamin D in the brain may not be as simple as presumed—specifically the difference between the levels in peripheral blood and intrathecal levels (in the cerebrospinal fluid around the spinal cord and brain):

“We here review current knowledge on the intrathecal vitamin D homeostasis in heath and disease, highlighting the need to assess vitamin D in the intrathecal compartment.”

What other evidence is there for a link between low levels of vitamin D and psychiatric diagnoses? A recent paper published in The Journal of Steroid Biochemistry and Molecular Biology examines the association between low vitamin D and psychiatric diagnoses in a group of Swedish patients. For 117 subjects serum 25-hydroxy-vitamin D (25-OHD) and plasma intact parathyroid hormone (iPTH) was collected, together with demographic data and psychiatric diagnoses.

“Their median 25-OHD was considerably lower than published reports on Swedish healthy populations. Only 14.5% had recommended levels…Patients with ADHD had unexpectedly low iPTH levels…having a diagnosis of autism spectrum disorder or schizophrenia predicted low 25-OHD levels. Hence, the diagnoses that have been hypothetically linked to developmental (prenatal) vitamin D deficiency, schizophrenia and autism, had the lowest 25-OHD levels in this adult sample, supporting the notion that vitamin D deficiency may not only be a predisposing developmental factor but also relate to the adult patients’ psychiatric state.”

And their data yielded another very relevant observation:

“This is further supported by the considerable psychiatric improvement that coincided with vitamin D treatment in some of the patients whose deficiency was treated.”

But how prevalent is vitamin D deficiency among American children? A paper published in the journal Pediatrics last year should serve as a reminder to both parents and doctors. The authors set out to…

“…determine the prevalence of 25-hydroxyvitamin D (25[OH]D) deficiency and associations between 25(OH)D deficiency and cardiovascular risk factors in children and adolescents.”

What did the data show? Even using a low reference range thatand is presently considered too low by most labs and has been updated:

“Overall, 9% of the pediatric population, representing 7.6 million US children and adolescents, were 25(OH)D deficient and 61%, representing 50.8 million US children and adolescents, were 25(OH)D insufficient.”

Even by outdated standards that amounts to 70% of the pediatric population in the US. Hence their conclusion:

“25(OH)D deficiency is common in the general US pediatric population and is associated with adverse cardiovascular risks.”

We can see from the above that the risks include brain health and development as well. How do you find out if your child’s (and your) vitamin D level is sufficient? Since individual genetic and circumstantial needs can vary so greatly, taking out the guesswork with a serum 25(OH)D (25-hydroxy vitamin D) test is best.

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Can gastrointestinal pathology be a contributing factor in neurodevelopmental disorders? Consider this study published in the American Journal of Gastroenterology in which the authors begin:

“Intestinal pathology, i.e., ileocolonic lymphoid nodular hyperplasia (LNH) and mucosal inflammation, has been described in children with developmental disorders. This study describes some of the endoscopic and pathological characteristics in a group of children with developmental disorders (affected children) that are associated with behavioral regression and bowel symptoms, and compares them with pediatric controls.”

They performed ileocolonoscopies and biopsies on 60 children whose diagnoses included Developmental diagnoses were autism (50 patients), Asperger’s syndrome (five), disintegrative disorder (two), attention deficit hyperactivity disorder (ADHD) (one), schizophrenia (one), and dyslexia (one). The tissue specimens were reviewed by three pathologists and compared with 22 well children and 2o with ulcerative colitis. Their data for GI pathology in the affected cohort were striking:

“Ileal LNH was present in 54 of 58 (93%) affected children and in five of 35 (14.3%) controls . Colonic LNH was present in 18 of 60 (30%) affected children and in two of 37 (5.4%) controls. Histologically, reactive follicular hyperplasia was present in 46 of 52 (88.5%) ileal biopsies from affected children and in four of 14 (29%) with UC, but not in non-IBD controls. Chronic colitis was identified in 53 of 60 (88%) affected children compared with one of 22 (4.5%) controls and in 20 of 20 (100%) with UC. Scores of frequency and severity of inflammation were significantly greater in both affected children and those with UC, compared with controls.”

Considering the impact of the enteric (gut) immune and nervous systems on the brain these findings are not a surprise. “When the gut is inflamed the brain is inflamed.” The authors conclude by stating:

“A new variant of inflammatory bowel disease is present in this group of children with developmental disorders.”

A paper published last year in the Canadian Journal of Gastroenterology adds to the discussion of this topic in regard to autism. The authors state:

“There have been several reports of a link between autism and chronic gastrointestinal symptoms. Endoscopy trials have demonstrated a higher prevalence of nonspecific colitis, lymphoid hyperplasia and focally enhanced gastritis compared with controls. Postulated mechanisms include aberrant immune responses to some dietary proteins, abnormal intestinal permeability and unfavourable gut microflora.”

The authors examined two autism spectrum disorder patients with chronic intestinal symptoms and abnormal endoscopies and reviewed relevant background studies. Their findings inspired this conclusion:

“While genetic susceptibility is an important contributor in ASDs, the exact etiology of these pervasive developmental disorders remains unclear and is most likely multi-factorial…Be it an immune-mediated connection, versus a ‘brain-gut axis’ interplay such as seen in irritable bowel syndrome, the increased prevalence of GI symptoms in this group of patients cannot be denied, nor the added distress that these symptoms could have on an individual who is already communicatively challenged…a heightened awareness and lower threshold for work-up and management of GI symptoms may help improve quality of life of these patients who may be suffering in silence.”

The authors of a paper published in the Journal of Neuroimmunology consider lymphocyte subsets and inflammatory cytokines in the gut in relation to autism:

“Gastrointestinal pathology, characterized by lymphoid nodular hyperplasia and entero-colitis, has been demonstrated in a cohort of children with autistic spectrum disorder (ASD).”

They assessed inflammation in the intestines of ASD children in comparison with well controls and children with Crohn’s disease by examining inflammatory cytokines present in CD3+ lymphocytes (T helper and cytotoxic T cells):

“In both peripheral blood and mucosa, CD3+ TNFα+ and CD3+ IFNγ+ [pro-inflammatory cytokines] were increased in ASD children compared with NIC [non-inflamed controls] and reached levels similar to CD [Crohn's disease]. In contrast, peripheral and mucosal CD3+ IL-10+ [anti-inflammatory cytokine] were markedly lower in ASD children with GI symptoms compared with both NIC and CD controls. In addition, mucosal CD3+ IL-4+ [pro-inflammatory] cells were increased in ASD compared with NIC.”

Again we see a marked pattern of gastrointestinal inflammation distinguishing the ASD group. The authors conclude:

“There is a unique pattern of peripheral blood and mucosal CD3+ lymphocytes intracellular cytokines, which is consistent with significant immune dysregulation, in this ASD cohort.”

Disorders of learning, behavior and neurodevelopment in childhood and adolescence are a heterogenous group with multiple possible causes so it would be an error to expect that all children with ASD have GI pathology and a principal or accessory cause. But it would be an equal error to fail to confirm whether or not it is a contributing factor in each individual case.

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There is a large body of evidence that compels us not to overlook hormonal dysregulation in ADHD and other disorders of learning, behavior and brain development. A paper published not long ago in the journal European Neuropsychopharmacology addresses the broad topic of neurosteroids. The authors state in regard to the steroid hormones active in the nervous system:

“Neurosteroids play a significant role in neurodevelopment and are involved in a wide variety of psychopathological processes…there is increasing evidence for their critical role from the early stages of brain development until adolescence.“

They proceed to review the involvement of neurosteroids in neurodevelopment and mental disorders in children and adolescents, noting in particular:

“Adequate physiological levels protect the developing neural system from insult and contribute to the regulation of brain organization and function. Neurosteroids may be involved in the pathophysiology and pharmacotherapy of a variety of disorders in children and adolescents, including schizophrenia, depression, eating disorders, aggressive behavior and attention deficit.”

A paper published in the journal Neuropediatrics examines the association of hypothalamo-pituitary-adrenal (HPA) axis dysfunction and intelligence performance:

“The aim of the present study was to examine the effects of hypothalamo-pituitary-adrenal (HPA) axis reactivity on intelligence test performance in subjects with attention-deficit/hyperactivity disorder (ADHD). We investigated the extent to which an increase or decrease in cortisol after stress was associated with the intelligence test performance in 68 clinic-referred children with ADHD.”

They administered a battery of tests for both assessment and stressor applications, plus…

“A saliva sample was collected from each subject before and after psychological testing in order to measure the level of cortisol in the saliva.”

Salivary cortisol is the most reliable and necessarily non-invasive way to measure functional cortisol levels as we know here from extensive clinical experience. Their data painted a striking picture:

“Decreases in the level of cortisol after the test were correlated with poor intelligence performance and the decrease of cortisol in respect to baseline significantly affected the verbal, performance and total IQ in subjects who showed blunted responses to stress.”

A fine study published recently in the Chinese Journal of Contemporary Pediatrics further investigates…

“…the function of the hypothalamus-pituitary-adrenal (HPA) axis in children with attention deficit hyperactivity disorder (ADHD).”

128 boys with ADHD at ages of 6 to 14 years were diagnosed and grouped according to the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV): ADHD-predominantly inattention type, ADHD-predominantly hyperactive impulsive type and ADHD-combined type. 30 healthy boys served as the control group. They tested cortisol and assessed intelligence level with Raven′s standard progressive matrices. What did the data show?

“The mean plasma cortisol level in the ADHD group was significantly lower than that in the control group. The three ADHD subgroups showed significantly decreased plasma cortisol level compared with the control group. The plasma level of cortisol was the lowest in the ADHD-HI group, followed by the ADHD-I group and the ADHD-C group.”

Their conclusion should be borne in mind by both clinicians and parents:

“In the non-stress state, the HPA axis may be dysfunctional in children with ADHD, which may be attributed to the under reactivity of the HPA axis. Lower plasma cortisol…may closely be related to attention deficit, hyperactivity and impulsive behaviors.“

More valuable research was published in the Yonsei Medical Journal (Korea) in which the authors state:

“Children with attention-deficit/hyperactivity disorder (ADHD) often perform poorly during cognitive tests. We sought to evaluate cortisol as potential moderator of performance in mentally challenging tasks in children with ADHD.”

They measured salivary cortisol in 90 children with ADHD before and after administration of a continuous performance test (CPT). Their data adds evidence that cortisol dysregulation in association with poorer performance can be either abnormally high or low:

“Children whose cortisol level increased after testing displayed a significantly longer response time and increased response time variability scores as compared to children who did not display increase of cortisol after the CPT test.”

Since activation of α1 adrenergic receptor mediates both cortisol level increase and attention impairment, they also conclude that in association with cortisol:

“The result of the current study suggests that stress-induced high norepinephrine (NE) release may accompany poorer attention performance in patients with ADHD.”

The authors of a paper published in European Child & Adolescent Psychiatry offer additional evidence that children with ADHD must be evaluated as individuals for varying patterns of cortisol dysregulation:

“The aim of this study was to investigate whether a different pattern of HPA axis activity is found between the inattentive (I) and combined (C) subtypes of ADHD, in comparison with healthy control children.”

They studied the effects of stress by comparing cortisol responses to a psychosocial stressor (a public speaking task). Their data revealed interesting differences:

“Children with ADHD-I showed an elevated cortisol response to the psychosocial stressor, in contrast to children with ADHD-C who showed a blunted cortisol response to the psychosocial stressor…hyperactivity symptoms were clearly related to a lower cortisol reactivity to stress. The results indicate that a low-cortisol responsivity to stress may be a neurobiological marker for children with ADHD-C, but not for those with ADHD-I.”

The authors of a paper published in the Journal of Attention Disorders draw our attention to the link between sensory hyperarousal and HPA axis dysregulation with their investigation of salivary cortisol levels:

“To determine if sensory overresponsivity (SOR) is a moderating condition impacting the activity of the Hypothalamic Pituitary Adrenal (HPA) Axis in children with ADHD.”

Children with ADHD and known SOR were compared with those with ADHD but without SOR and normal children, all of whom participated in a Sensory Challenge Protocol. Salivary cortisol was used as a measure of HPA activity with two prechallenge and seven postchallenge samples taken. Interestingly, their data showed…

“…a borderline significant difference found between the ADHDt [without SOR] and ADHDs [with SOR] group and a significant difference between ADHDt and the typical [normal] group.”

In other words, salivary cortisol measurements distinguished both ADHD groups from the normal group.

Clarification of the different patterns of HPA axis dysregulation in ADHD was reported in the Journal of Abnormal Child Psychology:

“Disruptions to hypothalamic-pituitary-adrenal (HPA) axis function have been associated with varying forms of psychopathology in children. Studies suggesting children with ADHD have blunted HPA function have been complicated by the prevalence of comorbid diagnoses and heterogeneity of ADHD. The goals of this research were to assess the relations between waking and stress–response salivary cortisol levels and comorbid disruptive behavior (DBD) and anxiety (AnxD) disorders and problems in boys with ADHD, and to examine whether cortisol levels varied across ADHD subtypes.”

The authors examined salivary cortisol on waking and in reaction to venipuncture (to determine stress-response levels), psychiatric symptoms and behavioral problems in 170 elementary school-age boys. The data left no doubt that there are dysfunctional subtypes of ADHD, emphasizing the importance of evaluating each child as an individual:

“Boys’ comorbid AnxD and anxiety problems were associated with greater cortisol reactivity, whereas boys’ comorbid DBD and oppositional problems predicted diminished adrenocortical activity. Reactive cortisol increases were greatest in boys with ADHD and comorbid AnxD, but without DBD…comorbid DBD predicted decreased cortisol reactivity in boys with inattentive and hyperactive subtypes of ADHD, but not in boys with combined subtype of ADHD. The results clarify previous patterns of distinct and divergent dysregulations of HPA function associated with boys’ varying kinds of psychopathology.”

By the way, note that venipuncture (drawing blood) was used elicit a cortisol-modifying stress response. This is one reason why we use saliva instead of blood tests for cortisol.

We can add to this a study published in the journal Child Psychiatry & Human Development that further examines HPA axis dysregulation in a specific subtype of ADHD. The authors set out…

“To investigate the hypothalamic pituitary adrenal (HPA) axis response to a stressor in adolescents with inattentive type attention-deficit hyperactivity disorder symptoms (ADHD-I).”

They too used salivary cortisol measurements as a metric in response to a social/cognitive stressor for threshold inattentive (TI), moderately inattentive (MI) and no symptom groups of healthy adolescents. A distinction was present in this study as well:

“The TI group displayed a significant decrease in cortisol post stressor whereas both the MI and comparison groups showed an increase in cortisol.”

We can also appreciate a study published in the journal Psychiatry Research that looks specifically at aggressive behavior and cortisol. The authors state:

“We examined the relationship between the cortisol response to stress and aggression in patients with attention deficit hyperactivity disorder (ADHD). Based on a report stating that only some of the patients with ADHD retain their hypothalamic-pituitary-adrenal axis reactivity to stress, we separately analyzed the relationship between aggression and the cortisol response to stress in two groups according to their reactivity to stress.”

Their data included psychological testing as a stress indicator with salivary cortisol measurements made before and after psychological test administration. Behavioral problems and aggression were assessed with the local (Korean) version of the Child Behavior Checklist. Their findings also showed the connection:

“The increase of the cortisol level was inversely correlated with aggression in patients who retained their reactivity to stress. The absolute value of the decrease was negatively correlated with the attention score of the CBCL for the patients who showed decreases in cortisol after stress. For the patients who showed increases in their concentration of cortisol in reaction to stress, cortisol may play a protective role against aggression.”

In other words, when cortisol went down aggression went up and attention scored worse. As we can see, there is a large body of evidence showing that we must consider the possibility of hypothalamic-pituitary-adrenal dysregulation in pediatric disorders of learning and behavior. This is best assessed by the functional approach that encompasses the multiple factors such as blood sugar dysregulation, inflammation from allergy or autoimmunity, etc. that can be contributing causes to HPA axis dysfunction, along with experienced assessment of salivary cortisol levels together with associated laboratory findings.

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GAD (glutamic acid decarboxylase) antibodies are expressed in type 1 (autoimmune) diabetes, adrenal failure (Addison disease), autoimmune thyroid diseases, premature ovarian failure, myasthenia gravis, pernicious anemia, Stiff-man syndrome and a number of other disorders. An informative study recently published in Acta Neurologica Scandinavica documents the link between these conditions and gluten sensitivity. The authors state:

“The high prevalence of gluten sensitivity in patients with stiff-person syndrome (SPS) lead us to investigate the relationship between gluten sensitivity and GAD-antibody-associated diseases.”

They used ELISA assays for GAD antibodies and serological markers of gluten sensitivity that generated compelling data:

“”Six of seven (86%) patients with SPS were positive for anti-GAD…This compared with 9/90 (11%) patients with idiopathic sporadic ataxia…16/40 (40%) patients with gluten ataxia…and 6/10 patients with type 1 diabetes only…”

Note that the serological tests for gluten sensitivity are a blunt instrument—only 40% of confirmed cases of gluten ataxia were recognized. The abundance of false negatives is why the gluten gene sensitivity test is so valuable.

Additionally, the authors found that…

“The titre of anti-GAD reduced following the introduction of a gluten-free diet in patients with SPS who had serological evidence of gluten sensitivity.”

Their conclusion is simply stated:

“These findings suggest a link between gluten sensitivity and GAD antibody-associated diseases.“

This study is especially interesting in connection with earlier research published in the journal Psychiatry. The authors set out to investigate the role of GAD antibodies in schizophrenia and related disorders:

“We hypothesized that GAD antibodies are increased in patients with chronic psychotic disorders. The aim of this pilot study was to compare the level of GAD antibodies in patients with chronic psychotic disorders with normal controls.”

By way of background they note that:

“The role of GABAergic neurotransmission in epilepsy, anxiety disorders, schizophrenia, and premenstrual dysphoric disorder has been a subject of some recent investigations. Absence of structural abnormalities in the brains of most patients with chronic psychotic disorders has always raised suspicion for an alternative pathogenesis and a possible functional disturbance at the neuronal/cellular level. Glutamic acid decarboxylase (GAD)…is involved in the formation of gamma aminobutyric acid (GABA) a central inhibitory neurotransmitter of the nervous system. Antibodies to GAD may impair GABA formation or inhibitory function.“

What did the data show?

“Serum levels of GAD antibodies in 12 patients with chronic psychotic disorders (schizophrenia and schizoaffective disorders) and 10 age-matched healthy control subjects were evaluated… Antibodies to GAD in patients with chronic psychotic disorders have a higher mean than nonpatient control individuals.”

The authors’ conclusion alerts the practitioner to be on the lookout:

“Antibodies to GAD65 are peripherally present in patients with chronic psychotic disorders (schizophrenia/schizoaffective disorders)... The presence of such antibodies also suggests a possible role for autoimmune mechanism in the pathogenesis of these disorders. In summary, from a practicing psychiatrist’s point of view, measurements of antibodies to GAD65 could potentially be used to screen for chronic psychotic disorders and for diabetes mellitus very early on in the disease process.”

GAD (glutamic acid decarboxylase) produces GABA, the most abundant inhibitory (calming) neurotransmitter in the body. Suboptimal levels can manifest as anxiety, insomnia, hyperarousal, panic, feeling overwhelmed, disorganized attention, restlessness, worry, tension, inner excitability, inability to relax, etc.

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An important research article was just published in PLoS One (Public Library of Medicine) that shows a connection between the disruption of dopamine neurons when a maternal infection causes the iron supply of the fetus to drop and schizophrenia. The authors give some background:

“Maternal infection during pregnancy has been associated with increased incidence of schizophrenia in the adult offspring. Mechanistically, this has been partially attributed to neurodevelopmental disruption of the dopamine neurons, as a consequence of exacerbated maternal immunity. In the present study we sought to target hypoferremia, a cytokine-induced reduction of serum non-heme iron, which is common to all types of infections. Adequate iron supply to the fetus is fundamental for the development of the mesencephalic dopamine neurons and disruption of this following maternal infection can affect the offspring’s dopamine function.”

The authors measured the adverse behavioral and neurochemical changes from challenging the dopamine circuits with turpentine to trigger an inflammatory immune response, both with and without maternal iron supplementation. They demonstrated that…

“Both the behavioral and neurochemical changes were prevented by maternal iron supplementation.“

We already know that iron is a critical nutrient for dopamine production in the adult. Their conclusion sums up why prenatal iron status is important in preventing neurodevelopmental disorders including schizophrenia in the offspring.

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There is a connection between how well you can smell, brain damage from autoimmune inflammation, and psychiatric disease. Consider this fascinating paper published in the journal Clinical Immunology in which the authors discuss the “inter-relationship between olfactory impairment, autoimmunity and neurological/psychiatric symptoms in several diseases affecting the central nervous system (CNS) such as Parkinson, Alzheimer’s disease, autism, schizophrenia, multiple sclerosis and neuropsychiatric lupus erythematosus. We suggest that common manifestations are not mere coincidences. Current data from animal models show that neuropsychiatric manifestations are intimately associated with smell impairment, and autoimmune dysregulation, via autoantibodies…”

In another paper published in the journal Autoimmunity Reviews the authors note that “Research in the field of immunology as well as in various brain illnesses is beginning to indicate the increasing relevance of smell in pathophysiology.” They further state “…evidence exists that there may be something unique about the olfactory system that is inextricably related to immunological function. In addition, accumulating evidence confirms the existence of olfactory dysfunction in brain disease, much of which appears at early stages including multiple sclerosis, Alzheimer’s Disease, Parkinson’s Disease, schizophrenia and depression…under certain circumstances, olfactory abnormalities may be associated with autoimmune conditions. Since the organization of the olfactory system is so sensitive, impairment may be noted at an early stage. This may become important in the prediction of certain brain illnesses.”

This paper recently published in the International Journal of Neuroscience focuses specifically on the link between olfaction, autoimmunity and Parkinson’s Disease. They first describe “the immune alterations observed in PD patients…the increase in the innate immune components including complement and cytokines within their substantia nigra and cerebrospinal fluid (CSF). These alterations extended to the adaptive immune response with the elevation of T cells and autoantibodies…in the peripheral blood and CSF of PD patients.” (Just the kinds of things we test for in the functional medicine approach.) They then describe the link between PD, autoimmunity and olfaction: “Smell deficit is one of the earliest signs of PD and a unique observation suggesting olfactory declines to be a consequence of autoimmune mechanisms.”

And the authors of this study published recently in the journal Autoimmunity observe that “Psychiatric diseases are often associated with mild alterations in immune functions (e.g., schizophrenia) as well as autoimmune features. Recent evidence suggests that autoimmune diseases (AD) demonstrate a higher prevalence of psychiatric disorders, such as depression and psychosis, than in the normal population. Patients with AD often have an olfactory impairment as well, based on smell studies… ” They report that olfactory gene receptors have brain functions in addition to smell, and go on to describe the genetic polymorphisms (variations) that link autoimmunity, psychiatric disorders and smell impairment.

The paper that concludes this post is tantalizingly entitled Olfaction—A Window to the Mind. Published not long ago in The Israel Medical Association Journal, it is available here in its entirety. The authors comment that “The sense of smell can provide a natural window to the brain. This window provides an opportunity to examine neural mechanisms and brain function in a non-invasive way.” They then undertake a fascinating review of the field of olfactory studies encompassing aspects ranging from autoimmunity and neuropsychiatric disease to sexual function, addiction, social behavior and the discrimination of self from non-self. Their conclusion is worth bearing in mind: “…assessment of the sense of smell and olfactory impairments is usually overlooked by patients and their clinicians. Given the clinical data reviewed here, clinicians should be encouraged to screen for olfactory impairments, which can help in the early diagnosis of CNS diseases such as Parkinson, dementia and schizophrenia, as well as CNS-autoimmune diseases such as neuropsychiatric lupus.”

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This paper just published in the Archives of General Psychiatry reports on a randomized, placebo-controlled trial that set out to “determine whether {omega}-3 PUFAs reduce the rate of progression to first-episode psychotic disorder in adolescents and young adults aged 13 to 25 years with subthreshold psychosis.” (PUFAs = polyunsaturated fatty acids) The omega-3s (fish oil) reduced progression to psychosis and improved function. The authors conclude: “Long-chain {omega}-3 PUFAs reduce the risk of progression to psychotic disorder and may offer a safe and efficacious strategy for indicated prevention in young people with subthreshold psychotic states.” I have found that we can predict who will benefit most from fish oil supplementation for psychiatric and neurological conditions with a fatty acid analysis, a blood test that measures the amounts and ratios of fatty acids in cell membranes.

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This review of the literature references over a hundred studies relevant to treating mental disorders by normalizing brain chemistry. It focuses on “the four most common mental disorders currently affecting America and other developed countries: major depression, bipolar disorder, schizophrenia, and obsessive compulsive disorder (OCD).” The authors conclude: “Proper medical diagnosis and a clear description of all possible treatment options should always be the first plan of action when treating mental disorders…New well-designed clinical studies are being published daily on the positive effects of nutritional and supplement therapies on all types of disorders and diseases...[Those] treating patients with mental disorders should be aware of available nutritional therapies, appropriate doses, and possible side effects…As with any form of treatment, nutritional therapy should be supervised and doses should be adjusted as necessary to achieve optimal results.”

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This important paper was published in the American Journal of Psychiatry. The authors state, “Thyrotoxicosis, celiac disease, acquired hemolytic anemia, interstitial cystitis, and Sjögren’s syndrome had higher prevalence rates among patients with schizophrenia,” and further conclude, “Schizophrenia is associated with a larger range of autoimmune diseases than heretofore suspected. Future research on comorbidity has the potential to advance understanding of pathogenesis of both psychiatric and autoimmune disorders.” In my experience, the autoimmune component must be recognized and treated. A couple related studies:

1. Vitamin D deficiency and schizophrenia published in Schizophrenia Bulletin in April, 2009
2. Gluten sensitivity and schizophrenia also in Schizophrenia Bulletin in June, 2009

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As you know, vitamin B12 is a critical nutrient for brain and nervous system health. Deficiencies commonly occur due to diet or poor assimilation. Here is a report published in the journal General Hospital Psychiatry describing a psychotic episode resulting from cobalamin (vitamin B12) deficiency. Interestingly, this occurred without any hematologic (blood) symptoms or preceding neurological manifestations. I have personally seen a case like the one described here.

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