Summary: chronic inflammation due to immune system dysregulation, with or without a diagnosed autoimmune disease, plays a fundamental role in chronic depression. This offers sustainable and evidence-based treatments for depression and brain health.

The authors of an important paper published in Current Immunology Reviews state:

…current antidepressants do not effectively target all of the pathological processes that are responsible for the major symptoms of depression…However, in recent years greater attention has been directed to the inter-relationship between the brain and peripheral organs (the” body-mind” connection) in which changes in the endocrine and immune systems play a major role in the pathological changes that occur in depression. Thus inflammation is beginning to emerge as a major contributing factor not only to depression and other major psychiatric disorders…”

Two major ways that immune dysfunction promotes depression are emphasized: the direct effect of inflammation on the brain, and the brain effects of the hormonal response to inflammation. Regarding the former:

“…in the past 30 years or so that clinical and experimental evidence has been obtained clearly demonstrating that aspects of both cellular and humoral immunity were dysfunctional in major depression…in particular the pro- and anti-inflammatory cytokines…Such clinical observations suggest that proinflammatory cytokines contribute to the major symptoms of depression and now forms the basis of the inflammation, cytokine or inflammatory response hypothesis of depression.”

It’s now known that peripherally derived inflammatory cytokines have access to the brain, including areas involved in depression…

“Once in the brain, the proinflammatory cytokines activated both neuronal and non-neuronal (for example, the microglia, astrocytes and oligodendroglia) cells via the nuclear factor-kappa-beta (NF-kB) cascade in a similar manner to that occurring in the peripheral inflammatory response…

Also, the production of serotonin and dopamine is adversely affected by inflammation:

“Recently much attention has been paid to the activation of the tryptophan-kynurenine pathway by these cytokines whereby tryptophan is shunted from the synthesis of serotonin to that of kynurenine…clearly this is an important mechanism whereby serotonergic function is decreased in depression. The activity of the dopaminergic system is also reduced in response to inflammation. For example, IFN reduces the synthesis of dopamine by decreasing the concentration of the co-factor tetrahydrobiopterin (BH4)…As IFN increases the synthesis of nitric oxide by activating the BH4 dependent enzyme nitric oxide synthase in the microglia it seems likely that the reduction in dopaminergic function is linked to the increase in nitric oxide. This gaseous neurotransmitter is known to activate the glutamatergic system which, when this exceeds physiologically limits, enhances apoptosis and neurodegeneration.”

In other words, an increase in inflammatory cytokines derails the production of serotonin and dopamine, and activates the excitatory (glutamatergic) system to the point of cell death.

Additionally, proinflammatory cytokines activate the HPA (hypothalamo-pituitary-adrenal) axis causing excessive cortisol production which is lethal to brain cells at high levels…

“In addition to the modulation of neurotransmitter function, proinflammatory cytokines contribute to the major symptoms of depression by activating the HPA axis by increasing the release of CRF, thereby contributing to hypercortisolaemia, a feature of major depression. The mechanism whereby the cytokines induce hypercortisolaemia involves a decreased sensitivity of the glucocorticoid receptors thereby leading to glucocorticoid resistance…”

The inflammation model also sheds light on the role of stress in depression:

“…as major depression is often accompanied by inflammatory diseases (such as irritable bowel syndrome, type 2 diabetes, arthritis and autoimmune disorders) that can activate the peripheral and central inflammatory response, it is possible that such inflammatory disorders initiate the inflammatory changes that precipitate depression….[But] it is evident that inflammation also occurs in depressed patients who are not suffering from concurrent inflammatory disorders. Thus the increased vulnerability of depressed patients to psychosocial stress is probably the key factor that leads to the activation of the immune and endocrine axes in depression. It is known, for example, that even the relatively mild acute stress of public speaking causes an increase in NF-kB activity, a key element in the induction of the inflammatory cascade. In this regard, it is also known that patients with major depression frequently show an enhanced responsiveness of IL-6 and NF-kB to an antigen challenge…such changes appear to be associated with activation of the microglia thereby suggestion that the inflammatory changes are also occurring in the brain.”

In other words, patients with major depression have a more pronounced inflammatory response to substances to which they are sensitized or allergic to (antigens). This is in addition to an increased immune and hormonal response to psychosocial stress.

Of special significance for the use of heart rate variability analysis for evaluation of the autonomic nervous system and therapies that increase parasympathetic tone…

“The mechanism whereby psychological stress influences both the peripheral and central inflammatory cascade is co-ordinated by the autonomic nervous system. Thus the release of noradrenaline and adrenaline following the activation of the sympathetic system results in the activation of both alpha and beta adrenoceptors on immune cells thereby initiating the release of proinflammatory cytokines, via the activation of the NF-kB cascade, particularly on macrophages and monocytes in peripheral blood…Conversely stimulation of the parasympathetic system has the opposite effect on the stress induced inflammatory response…It is possible that the anti-depressant-like action of vagal nerve stimulation, occasionally used to treat resistant depression, is associated with such an anti-inflammatory action.”

Brain inflammation associated with depression actually causes the death of brain cells (apoptosis):

“Thus in major depression, the prolonged activation of the inflammatory network in the brain results in a decrease in neurotrophins, leading to reduced neuronal repair, a decrease in neurogenesis, and an increased activation of the glutamatergic pathway that contributes to neuronal apoptosis, oxidative stress and the induction of apoptosis in astrocytes and oligodendrocytes.”

On top of all this, inflammation causes the biochemical pathway that produces serotonin from tryptophan to converted to the production of neurotoxins instead through the tryptophan-kynurenine pathway and the production of quinolinic acid.

“As both the cytokines and cortisol are raised in major depression, it is not surprising to find that the tryptophan-kynurenine pathway is increased….Kynurenine hydroxylase metabolises kynurenine first to 3-hydroxykynurenine and then to 3-hydroxyanthranilic acid and quinolinic acid. This pathway is increased in depression and dementia…In chronic depression…the activated microglia produce an excess of the neurotoxin…Furthermore quinolinic acid can cause apoptosis of the astrocytes. This results in a reduction in the metabolic and physical buffer to the neurons that is usually provided by the astrocytes and thereby further exposes the neurons to the neurodegenerative actions of quinolinic acid.”

Inflammation in the brain over the long term causes neurodegeneration that appear as brain shrinkage:

“The structural changes observed in the brain of patients with chronic depression lends support to the neurodegenerative hypothesis of depression. It is known that there is a shrinkage of the hippocampus in patients with major depression and a decrease in the number of astrocytes and a neuronal loss in the prefrontal cortex and in the striatum. Such changes could be the consequence of chronic low grade inflammation in which the proinflammatory cytokines, nitric oxide, prostaglandin E2 and other inflammatory mediators play key roles; the cytokines are known to induce the cyclo-oxygenase and nitric oxide sythase pathways in the brain and thereby increase the inflammatory insult. The inhibition of neurotrophin synthesis in the brain by glucocorticoids, and the neurotoxic action of quinolinic acid, add further to the impact of the inflammatory changes.”

There are indications that patients who respond poorly to neurotransmitter-manipulating medications have markers for increased inflammation:

“Further evidence for the relationship between inflammation and depression is provided by the observation that depressed patients with a history of partial or lack of response to antidepressant treatments have elevated plasma concentrations of IL-6 and acute phase proteins that persist despite antidepressant treatment. It has been suggested that patients who are resistant to conventional antidepressant treatment possess abnormal alleles of the IL-1 and TNF genes, and possibly for T-cell function.”

Moreover, even when there is some relief from a depressed mood or anxiety with these medications…

“…there is abundant clinical evidence that the available antidepressants…are far less effective in treating the memory and cognitive dysfunction (fatigue, psychomotor retardation) that commonly affect middle aged and elderly depressed patients.”

There is mounting evidence that modulating inflammation can improve the inflammatory response:

“There are already indications from the clinical literature that TNF antagonists…reduce the symptoms of depression in a variety of patients with autoimmune diseases…the mood state of the patients improving before the signs of improvement of the autoimmune disorder…IL-10, and insulin-like growth factor that has prominent anti-inflammatory activity, have been shown to attenuate the depressive-like behaviour in rodents induced by an inflammatory challenge.”

IL-10 is increased by correcting suboptimal levels of vitamin D.

“Perhaps the most obvious step to the reduction of inflammation both centrally and peripherally is to reduce the activity of the prostenoid pathway and thereby reduce the synthesis of inflammatory prostaglandins such as PGE2.”

This is exactly what is accomplished by correcting an omega-3 fatty acid deficiency with a low 3:6 ratio.

The best chance for a sustainable program for helping depression by treating the inflammation is to determine with the appropriate tests why the excessive inflammation is happening in the first place. Then physiological and sustainable treatments can address those underlying causes properly. That brings up the very large topic of the functional management of autoimmune disease and chronic inflammation, a subject of many posts here and deserving of a weighty textbook. See posts forthcoming in the next week on the role of gastrointestinal inflammation as a contributing cause and treatment target for depression and the effectiveness of the omega-3 fatty acid EPA as a PGE2 reducer for depression.

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“When the gut is inflamed, the brain is inflamed” is a guideline that clinicians should bear in mind, and depression is one possible expression of brain inflammation. A study just published in the journal Digestive and Liver Disease offers evidence that inflammatory reactions to gluten can increase the risk for suicide. The authors state:

“Individuals with coeliac disease have increased risk of depression and death from external causes, but conclusive studies on death from suicide are missing. We examined the risk of suicide in coeliac disease and amongst individuals where the small intestinal biopsy showed no villous atrophy.”

The authors collected biopsy data on 29,083 individuals (from all 28 clinical pathology departments in Sweden) 1969–2007 who had celiac disease with villous atrophy (eroded gut lining), and another 13,263 who had non-celiac gluten sensitivity (inflammation but without villous atrophy), and 3719 subjects with positive coeliac disease lab results but normal mucosa. They the calculated Hazard ratios for suicide as recorded in the Swedish Cause of Death Register. What did their data show?

“The risk for suicide was higher in patients with coeliac disease compared to general population controls (HR = 1.55; based on 54 completed suicides). Whilst suicide was also more common amongst individuals with inflammation (HR = 1.96), no such increase was seen amongst individuals with a normal mucosa but positive coeliac disease serology.”

In other words, their data showed a 96% increase in risk for suicide among those with gluten sensitivity who had gut inflammation. These findings are in keeping with the extensive evidence for brain inflammation as a factor in depression and the linked between microinflammati0n in the gut and destructive glial activity in the brain. The authors conclude with an exhortation to practitioners:

“We found a moderately increased risk of suicide amongst patients with coeliac disease. This merits increased attention amongst physicians treating these patients.”

Note: Many diagnoses are missed due to inadequate laboratory resources. Only Cyrex Labs currently offers a complete gluten sensitivity test panel.

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Imbalances or deficiencies in essential fatty acids which are critical brain components can contribute to depression and neurological disorders. A study just published online in the journal Acta Pædiatrica delineates the decisive difference they make in adolescents. The authors set out to…

“…study the relationship between polyunsaturated fatty acids (PUFA) status and depression in adolescents with eating disorders (ED) and weight loss.”

They measured essential fatty acids (FA) in the red blood cell membranes of 217 adolescents with eating disorders. As the clinicians reading this know, erythrocyte fatty acids also reflect the fatty acid status of the brain. The study subjects were also examined for depression by clinical interviews and psychological self-report instruments. A clear-cut picture emerged from the data:

“Adolescents with ED and depression did not differ from those with ED only in terms of age, BMI, weight loss and duration of disease. In their FA profile depressed adolescents had lower proportions of eicosapentanoic acid (EPA) and docosahexanoic acid (DHA), the end products of the ω3 PUFA series. The ratio of long chain (>18 carbons) ω6/ω3 PUFA was therefore higher in depressed adolescents. Indices of desaturase activites did not differ between depressed and not depressed adolescents.”

In other words, the only difference among the factors examined in this study between the adolescents with and without depression  was their essential fatty acid status. Thus the authors conclude:

“Low ω3 status is related to depression in adolescents with ED. This cannot be explained by differences in weight (loss) and duration of disease, nor by differences in PUFA processing by desaturases. Data suggest a lower dietary intake of ω3 PUFA in those with depression. Further investigations should determine whether ω3 PUFA status improves by refeeding only or whether supplementation with PUFA is warranted.”

See also the Parents’ Guide To Brain Health for additional evidence of the role of fatty acids, along with information on the other important aspects.

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More evidence for the profound effects of light therapy is offered in a randomized placebo-controlled trial published recently in the Archives of General Psychiatry that documents the effectiveness of bright light therapy for relieving depression. The authors first observe:

“Major depressive disorder (MDD) in elderly individuals is prevalent and debilitating. It is accompanied by circadian rhythm disturbances associated with impaired functioning of the suprachiasmatic nucleus, the biological clock of the brain. Circadian rhythm disturbances are common in the elderly. Suprachiasmatic nucleus stimulation using bright light treatment (BLT) may, therefore, improve mood, sleep, and hormonal rhythms in elderly patients with MDD.”

They went about testing their assumption with a double-blind, placebo-controlled randomized clinical trial of bright light treatment (BLT) with 89 subjects age 60 or above living in the Amsterdam region who suffered from MDD. Treatment consisted of three weeks of 1-hour early-morning BLT (pale blue, approximately 7500 lux) vs placebo (dim red light, approximately 50 lux). They were assessed for the degree of depression at baseline (T0), after 3 weeks of treatment (T1), and 3 weeks after the end of treatment (T2) with the Hamilton Scale for Depression and cortisol and melatonin levels. As for the results:

“Intention-to-treat analysis showed Hamilton Scale for Depression scores to improve with BLT more than placebo from T0 to T1 (7%) and from T0 to T2 (21%). At T1 relative to T0, get-up time after final awakening in the BLT group advanced by 7%, sleep efficiency increased by 2%, and the steepness of the rise in evening melatonin levels increased by 81% compared with the placebo group. At T2 relative to T0, get-up time was still advanced by 3% and the 24-hour urinary free cortisol level was 37% lower compared with the placebo group. The evening salivary cortisol level had decreased by 34% in the BLT group compared with an increase of 7% in the placebo group.”

Remember, this is not seasonal affective disorder (SAD) but non-seasonal major depression. It’s also noteworthy that beneficial effects could still be measured three weeks after the end of treatment. The authors conclude:

“In elderly patients with MDD, BLT improved mood, enhanced sleep efficiency, and increased the upslope melatonin level gradient. In addition, BLT produced continuing improvement in mood and an attenuation of cortisol hyperexcretion after discontinuation of treatment.“

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A study published in the Archives of General Psychiatry illustrates an important aspect of the biological component of depression. The authors set out to…

“…test the hypothesis that reduced hippocampal volume precedes and therefore may be implicated in the onset of depression.”

The hippocampus is the ‘seat’ of short-term memory and regulates the adrenal rhythm of cortisol. It’s well known that the hippocampal shrinkage occurs due to damage from high levels of cortisol that can occur in reaction to inflammation (autoimmune and allergic), blood sugar dysregulation and other stress demands. The authors examined 55 girls aged 9-15 years with voxel-based morphometry brain matter density estimates and traced hippocampal volume (MRI), 23 were high risk because of a maternal history of depression. What did the data show?

“Voxel-based morphometry analyses indicated that individuals at high risk of depression had significantly less gray matter density in clusters in the bilateral hippocampus than low-risk participants. Tracing yielded a volumetric reduction in the left hippocampus in the high-risk participants.”

This is why factors that have an adverse effect on hippocampal integrity always considered in the functional approach to depression as noted in the Parents’ Guide to Brain Health. The authors conclude:

“Compared with individuals at low familial risk of the development of depression, high-risk individuals have reduced hippocampal volume, indicating that neuroanatomic anomalies associated with depression may precede the onset of a depressive episode and influence the development and course of this disorder.”

The most dependable way to know whether there are abnormalities in the regulation of cortisol amplitude and rhythm that may be associated with hippocampal damage is by easily measuring the free-fraction (bioactive) cortisol levels in four saliva samples easily collected over the day.

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Another outcome study to add to the massive body of evidence that the psychopharmaceutical model for treating depression is seriously flawed was published in the journal Psychosomatic Medicine. The authors pitted sertraline (Zoloft, an SSRI) against exercise and placebo as they set out to…

“…assess whether patients receiving aerobic exercise training performed either at home or in a supervised group setting achieve reductions in depression comparable to standard antidepressant medication (sertraline) and greater reductions in depression compared to placebo controls.”

They randomly assigned 202 adults diagnosed with major depression were to either supervised exercise in a group setting; home-based exercise; antidepressant medication (sertraline, 50–200 mg daily); or placebo pill for 16 weeks. This was followed by a structured clinical interview for depression and completed the Hamilton Depression Rating Scale (HAM-D). Typically, the data showed little difference between the placebo and Zoloft, and virtually no difference between the medication and exercise:

“After 4 months of treatment, 41% of the participants achieved remission, defined as no longer meeting the criteria for major depressive disorder (MDD) and a HAM-D score of <8. Patients receiving active treatments tended to have higher remission rates than the placebo controls: supervised exercise = 45%; home-based exercise = 40%; medication = 47%; placebo = 31%. All treatment groups had lower HAM-D scores after treatment; scores for the active treatment groups were not significantly different from the placebo group.”

There is an enormous amount of science showing that this class of medications profoundly perturbs the brain in such a way that attempting to stop taking them after 6 weeks or continuing them long-term can result in the dismal trap of a brain sensitized to depression. This study would have been even more striking had they compared the unmedicated exercise group to those who were medicated after attempting to stop. As it is, the authors conclude:

“The efficacy of exercise in patients seems generally comparable with patients receiving antidepressant medication and both tend to be better than the placebo in patients with MDD. Placebo response rates were high, suggesting that a considerable portion of the therapeutic response is determined by patient expectations, ongoing symptom monitoring, attention, and other nonspecific factors.”

Historically, before the age of psychopharmaceuticals most cases of major depression tended to be self-limiting. For an objective, meticulous, articulate and gripping scientific and historical narrative on how anti-depressants, tranquilizers and anti-psychotic medications have promoted the skyrocketing levels of mental disability, I suggest Anatomy of an Epidemic by Robert Whitaker. Anyone considering taking or prescribing these medications should be aware of the science reviewed comprehensively in this text.

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A sobering study just published in the Archives of General Psychiatry offers evidence that young children with ADHD are at increased risk of serious depression and suicide. The authors set out…

“To test the hypothesis that young children with attention-deficit/hyperactivity disorder (ADHD) are at increased risk for depression and suicidal ideation and attempts during adolescence and to identify early predictors of which young children with ADHD are at greatest risk.”

They examined 125 children diagnosed with ADHD at 4 to 6 years of age and compared them with 123 demographically matched children without ADHD. The children were followed with multiple diagnostic assessments of depression and suicidal behavior from 9 through 18 years of age. What did the data show?

“Children with ADHD at 4 to 6 years of age were at greatly increased risk for meeting DSM-IV criteria for major depression or dysthymia and for attempting suicide through the age of 18 years relative to comparison children…Within the ADHD group, children with each subtype of ADHD were at risk but for different adverse outcomes. Girls were at greater risk for depression and suicide attempts.”

Incidentally…

“Maternal depression and concurrent child emotional and behavior problems at 4 to 6 years of age predicted depression and suicidal behavior.”

This is a public health alarm of the highest order. Clinicians and parents who bear the authors’ conclusion in mind will want to vigorously pursue a functional approach to identifying and treating the underlying causes of ADHD:

“All subtypes of ADHD in young children robustly predict adolescent depression and/or suicide attempts 5 to 13 years later. Furthermore, female sex, maternal depression, and concurrent symptoms at 4 to 6 years of age predict which children with ADHD are at greatest risk for these adverse outcomes. Identifying high-risk young children with ADHD sets the stage for early prevention trials to reduce risk for later depression and suicidal behavior.”

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While celiac disease often goes undiagnosed, failure to recognize the non-celiac manifestations of gluten sensitivity is widespread. The neurological effects can contribute to disorders of learning, behavior and neurodevelopment even in the absence of intestinal symptoms. The authors of a study published in the Journal of Attention Disorders observe:

“Several studies report a possible association of celiac disease (CD) with psychiatric and psychological disturbances, such as ADHD.”

They examined 132 subjects affected by CD for ADHD symptoms by behavioral scale before and 6 months after a gluten-free diet was started, and found that:

“The overall score improved significantly as well as most of the ADHD-like symptomatology specific features (Bonferroni-corrected, paired-sample t tests).”

They state in their conclusion:

“The data indicate that ADHD-like symptomatology is markedly overrepresented among untreated CD patients and that a gluten-free diet may improve symptoms significantly within a short period of time. The results of this study also suggest that CD should be included in the list of diseases associated with ADHD-like symptomatology.”

Remember, as the authors of a paper published by GeneReviews state:

“Classic celiac disease, characterized by mild to severe gastrointestinal symptoms, is less common than nonclassic celiac disease, characterized by absence of gastrointestinal symptoms.”

The report on a study published in the journal Psychosomatics begins with the observation:

“A high prevalence of depressive symptoms, hypothetically related to serotonergic dysfunction, has been reported among adults with celiac disease. The authors used semistructured psychiatric interviews and symptom measurement scales to study mental disorders in 29 adolescents with celiac disease and 29 matched comparison subjects.

The also observe in review of the existing evidence:

“Patients with celiac disease may suffer from neurological symptoms, such as peripheral neuropathy, ataxia, intellectual deterioration, brain atrophy, and epilepsy…In addition to neurological manifestations, a significantly higher prevalence of depressive symptoms (30–69%) and depressive disorders (42%) has been reported in adult celiac disease patients, compared to medical and normal comparison subjects…Improvement in depressive disorders has been described in some celiac disease patients after they started a gluten-free diet.“

What did their findings show specifically in regard to adolescents?

“We found that celiac disease was associated with higher lifetime prevalences of major depressive disorder and disruptive behavior disorder in adolescents…at least in some of these patients major depression and disruptive behavior disorder were related to celiac disease and alleviated by treatment of celiac disease with a gluten-free diet.”

The clinical implications of the data are summarized in their conclusion:

“Celiac disease is associated with increased prevalence of depressive and disruptive behavior disorders in adolescents, particularly in the phase before diet treatment. In some cases psychiatric symptoms appear to improve after the patient starts a gluten-free diet. The possibility of undiagnosed celiac disease should be taken into account in the differential diagnosis of these disorders, since the diet treatment is essential.“

Interestingly, in light of the reports that follow, they also make this observation:

“The risk of psychological disorders is substantially higher in children with a chronic disease and, for unknown reasons, particularly in patients with inflammatory bowel disease.“

What are the mechanisms by which gluten sensitivity can contribute to neurodevelopmental disorders? A study published in the Journal of Clinical Immunology examines gut mucosal immunopathology in relation to regressive autism:

“Inflammatory intestinal pathology has been reported in children with regressive autism (affected children). Detailed analysis of intestinal biopsies in these children indicates a novel lymphocytic enterocolitis with autoimmune features…”

The authors undertook a detailed analysis of mucosal infiltrate with flow cytometry (inspected the cellular components of gut lining secretions) and intestinal biopsies, and…

“…found a prominent mucosal eosinophil [allergen-reactive white blood cell] infiltrate in affected children that was significantly lower in those on a gluten- and casein-free diet… The data provide further evidence of a pan-enteric mucosal immunopathology in children with regressive autism that is apparently distinct from other inflammatory bowel diseases.”

Antibodies to neuronal tissues, signaling molecules and key enzymes can also play a role in neurological disorders associated with gluten sensitivity. The authors of a paper published in the journal Acta Neurologica Scandinavica 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.”

GAD is glutamic acid decarboxylase, aka glutamate decarboxylase. Most clinicians reading this are aware that GAD is a target for autoantibodies in type 1 diabetes, but may not recall that it is required to convert glutamate into GABA, our most abundant inhibitory (calming) neurotransmitter. Functional deficiencies of GABA can manifest as anxiety, restlessness, disorganized attention, inner excitability and tension with difficulty relaxing, feeling overwhelmed, worry, etc. The authors used ELISA assays for anti-GAD and for serological markers of gluten sensitivity in patients recruited from clinics based at the Royal Hallamshire hospital, Sheffield, UK. Those with gluten sensitivity were followed up after the introduction of a gluten-free diet. Their data painted a compelling picture:

“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…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. The same was observed in patients with gluten ataxia and anti-GAD antibodies. This was also associated with clinical improvement.“

Parents of patients and the practitioners caring for them should bear their conclusion in mind:

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

Interestingly, impairment in the ability to digest gliadin (from gluten), a problem which has a genetic basis, can contribute to affective disorders. The authors of a paper published in Behavioral and Brain Functions offer evidence from an investigation of the urine of depressed patients for relevant undigested peptides:

“We find overlapping patterns of peptide peaks in severe depression, but with considerable individuality. Mass spectrometry shows that some of these peptides are probably of dietary origin, because their sequences are found only in certain dietary proteins. Opioids from casein and gliadin are typical examples.“

Their conclusion is part of the rationale for offering specific digestive enzymes (peptidases) to patients with gluten sensitivity:

“Peptide increase in urine is found when break down is deficient, and the data presented agree with reports on peptidase deficiencies in depression.”

Another mechanism by which gluten can promote autoimmune disorders with neurological, behavioral and neurodevelopmental consequences is by causing abnormal permeability (‘leakiness’) of the intestinal mucosal barrier. This causes the gut-associated immune tissue to be abnormally exposed to the intestinal contents. The authors of a paper published recently in the Annals of the New York Academy of Sciences examine the link between intestinal permeability and autoimmune disease:

“Interestingly, recent data suggest that gliadin is also involved in the pathogenesis of T1D. There is growing evidence that increased intestinal permeability plays a pathogenic role in various autoimmune diseases including CD and T1D. Therefore, we hypothesize that besides genetic and environmental factors, loss of intestinal barrier function is necessary to develop autoimmunity.”

In delineating the process by which exposure to antigen in the gut triggers a genetic susceptibility, they note:

“In all cases, increased permeability precedes disease and causes an abnormality in antigen delivery that triggers immune events, eventually leading to a multiorgan process and autoimmunity.”

Moreover…

“Alterations in the intestinal balance between beneficial and potentially harmful bacteria have also been associated with allergy, type 1 diabetes and inflammatory bowel diseases…”

These factors come to a point that disrupts the tight junctions (TJ) of the intestinal barrier by perturbing the production of zonulin, an agent involved in loss of barrier function and autoimmune disease:

“The zonulin upregulation during the acute phase of CD was confirmed by measuring zonulin concentration…Compared to healthy controls, CD subjects showed significantly higher zonulin serum concentrations during the acute phase of the disease that decreased following a gluten-free diet…Similar results were obtained from T1D subjects…Our group has generated evidence that gliadin induces increased intestinal permeability by releasing preformed zonulin…When exposed to luminal gliadin, intestinal biopsies from celiac patients in remission expressed a sustained luminal zonulin release and increase in intestinal permeability.”

They summarize their findings with this important statement:

“Genetic predisposition, miscommunication between innate and adaptive immunity, exposure to environmental triggers, and loss of intestinal barrier function secondary to dysfunction of intercellular TJ all seem to be key components in the pathogenesis of autoimmune diseases. Both in CD and T1D gliadin may play a role in causing loss of intestinal barrier function and/or inducing the autoimmune response in genetically predisposed individuals…Since TJ dysfunction allows this interaction, new therapeutic strategies aimed at re-establishing the intestinal barrier function offer innovative, unexplored approaches for the treatment of these devastating diseases.”

Further confirmation of the damage gliadin does to the intestinal epithelial barrier is offered in a paper published in the Scandinavian Journal of Gastroenterology:

“We investigated whether gliadin has any immediate effect on zonulin release and signaling.”

They exposed human intestinal tissue to gliadin and evaluated zonulin release and barrier permeability by PCR (polymerase chain reaction) and immunofluorescence microscopy. They too documented similar effects:

“When exposed to luminal gliadin, intestinal biopsies from celiac patients in remission expressed a sustained luminal zonulin release and increase in intestinal permeability…”

However, they found that non-celiac patients also exhibited an increased zonulin release that, while not the magnitude of the celiac patients, caused intestinal permeability:

“…biopsies from non-celiac patients demonstrated a limited, transient zonulin release which was paralleled by an increase in intestinal permeability…”

This would be an argument in favor of everyone adopting a gluten-free diet. The authors’ conclusion is striking:

“Based on our results, we concluded that gliadin activates zonulin signaling irrespective of the genetic expression of autoimmunity, leading to increased intestinal permeability to macromolecules.”

The authors of a study published in the journal Gastroenterology add to the body of knowledge by identifying the mechanism by which gluten increases zonulin release and intestinal permeability:

“Celiac disease is an immune-mediated enteropathy triggered by gliadin, a component of the grain protein gluten. Gliadin induces an MyD88-dependent zonulin release that leads to increased intestinal permeability…We aimed to establish the molecular basis of gliadin interaction with intestinal mucosa leading to intestinal barrier impairment.“

They demonstrated that the chemokine receptor CXCR3 binds gliadin by examining CXCR3 protein and gene expression in intestinal epithelial cell lines and biopsy specimens, and gliadin-CXCR3 interaction by immunofluorescence microscopy, laser capture microscopy, real-time reverse-transcription polymerase chain reaction, and immunoprecipitation/Western blot analysis. On a positive note, the observed that…

“Gliadin binds to CXCR3 and leads to MyD88-dependent zonulin release and increased intestinal permeability…[however] Mucosal CXCR3 expression was elevated in active celiac disease but returned to baseline levels following implementation of a gluten-free diet.“

What about evidence that following a gluten-free diet helps with behavioral disorders of children and adolescents? The authors of a study published in BMC (BioMed Central) Psychiatry state:

“Coeliac disease in adolescents has been associated with an increased prevalence of depressive and disruptive behavioural disorders, particularly in the phase before diet treatment. We studied the possible effects of a gluten-free diet on psychiatric symptoms, on hormonal status (prolactin, thyroidal function) and on large neutral amino acid serum concentrations in adolescents with coeliac disease commencing a gluten-free diet.”

Moreover…

“Coeliac disease is an under-diagnosed autoimmune type of gastrointestinal disorder… Non-specific symptoms such as fatigue and dyspepsia are common, but the disease may also be clinically silent….Undetected or neglected, coeliac disease is associated with serious complications…depressive and disruptive behavioural disorders are highly common also among adolescents, particularly in the phase before diet treatment…Recently 73% of patients with untreated coeliac disease – but only 7% of patients adhering to a gluten-free diet – were reported to have cerebral blood flow abnormalities similar to those among patients with depressive disorders.“

They assessed adolescents aged 12 to 16 years with several symptom scales and followed them at intervals after starting a gluten-free diet. What did their data show?

“Adolescent coeliac disease patients with depression had significantly lower pre-diet tryptophan/ competing amino-acid (CAA) ratios and free tryptophan concentrations, and significantly higher biopsy morning prolactin levels compared to those without depression. A significant decrease in psychiatric symptoms was found at 3 months on a gluten-free diet compared to patients’ baseline condition, coinciding with significantly decreased coeliac disease activity and prolactin levels and with a significant increase in serum concentrations of CAAs.”

Parents and clinicians should consider their conclusions:

“…since diet treatment may alleviate psychiatric symptoms, and earlier diagnosis may have beneficial effects on psychological and even on neurobiological vulnerability to depression, the possibility of psychiatric complications of coeliac disease needs to be taken into account in differential diagnosis of depressive and behavioural disorders.”

A paper published in the journal Nutritional Neuroscience suggests similar indications for some children with autism spectrum disorders:

“There is increasing interest in the use of gluten- and casein-free diets for children with autism spectrum disorders (ASDs). We report results from a two-stage, 24-month, randomised, controlled trial incorporating an adaptive ‘catch-up’ design and interim analysis.”

They randomly assigned 72 Danish children to two diets and examined them for inattention and hyperactivity at baseline, 8 and 12 months. At that point there data showed that…

“…there was a significant improvement to mean diet group scores (time*treatment interaction) on sub-domains of ADOS, GARS and ADHD-IV measures. Surpassing of predefined statistical thresholds as evidence of improvement in group A at 12 months sanctioned the re-assignment of group B participants to active dietary treatment.”

The authors state in their conclusion:

“Our results suggest that dietary intervention may positively affect developmental outcome for some children diagnosed with ASD.”

What is the practical bottom line for parents and practitioners? There is mounting scientific evidence that the possibility of gluten sensitivity should not be overlooked when investigating the contributing causes to childhood disorders of learning, behavior and neurodevelopment. Given that celiac disease can be ‘silent’, and that we are particularly concerned with the non-celiac neurological manifestations of gluten sensitivity, testing for the genetic susceptibility in addition to anti-gliadin antibodies is a clinically prudent course of action.

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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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Thyroid dysfunction is not to be overlooked as a possible contributing cause to problems with learning, behavior and brain development. It can be expressed in a variety of ways, often requiring a nuanced functional analysis to detect and solve the problem. A study published in the journal Brain Research discusses an often overlooked type of thyroid dysregulation that can contribute to ADHD. The authors state:

“Attention deficit disorders are a frequent manifestation of resistance to thyroid hormone (RTH), a disorder caused by mutations in the hormone-binding domain of the human thyroid hormone receptor β gene.”

They used PET scans to measure cerebral glucose metabolism in regions of the brain involved in attention, comparing normal subjects to those with RTH. A clear-cut difference was observed:

“Compared to the control group, performance on a continuous auditory discrimination task was severely impaired in the RTH subjects, while metabolism was higher both in the right parietal cortex and the anterior cingulate gyrus. Abnormally high functional activity of the anterior cingulate during sustained attention may be associated with a decreased signal-to-noise ratio for the neural processing of task stimuli in subjects with RTH.“

In other words, resistance to thyroid hormone was associated with impaired function in the parts of the brain that are active in paying attention to and processing what we are trying to listen to. Other parts of the brain went into ‘hyperdrive’ in an attempt to compensate. Remember that this type of thyroid dysfunction, peripheral resistance to thyroid hormone, will appear normal on the usual lab tests.

A paper published in Pediatric Neurology directs our attention to the disruption of learning and behavior caused by subclinical hyperthyroidism—’subclinical’ meaning that no other overt signs of hyperthyroid are clinically apparent. The authors…

“…report three children who exhibited developmental learning disabilities (DLDs) associated with behavioral disturbances, such as attention deficit, hyperactivity, and autistic features. The thyroid function tests performed as a part of routine endocrinologic evaluation of children with DLDs revealed a hormonal profile consistent with hyperthyroidism. These children had no systemic signs of hyperthyroidism.”

Though it may not be the most sustainable long-term therapy from a functional perspective, they treated with medication to suppress thyroid hormone synthesis and reported that it…

“…resulted in good control of their hyperkinetic behavior and subsequent improvement in language function attributable to an increased attention span, thereby facilitating speech therapy.”

Although only a subset of children with learning and behavioral disorders will be found to found to have subclinical hyperthyroidism, it is a possibility that should be borne in mind and ‘crossed off the list’. The authors state:

“Although routine screening of all children with DLDs for thyroid dysfunction may not be cost-effective, selective screening of children with familial attention-deficit hyperactivity disorder and those with attention-deficit and hyperactivity in association with DLDs and pervasive developmental disorders appears to be justified.”

Another study published in the journal Psychoneuroendocrinology draws our attention to functional disturbances in thyroid hormone regulation from a different perspective. The authors state:

“Thyroid abnormalities have been associated with attention deficit/hyperactivity disorder (ADHD) and with other childhood psychiatric disorders. The goal of this study was to determine the relationships between thyroid hormone concentrations, neurocognitive functioning, and psychiatric diagnosis in children.”

They examined 338 children referred to a clinic for learning and behavior problems, measuring their thyroid stimulating hormone (TSH) levels and free thyroxine index (FT4I) and correlating them with diagnostic and descriptive information. Not surprisingly, the data showed that it was the more subtle functional abnormalities rather than gross pathologic ones that discriminated different types of ADHD:

“Thyroid abnormalities were uncommon in children referred for ADHD. After excluding children with thyroid disease, there was a greater proportion with low concentrations of normal FT4I for ADHD–Predominantly Inattentive type, but not for ADHD–Combined Type. High concentrations of normal FT4I were associated with mood lability, preoccupations, and lower ratings of attention problems. Thyroxine concentrations within the normal range were differentially associated with ADHD–Combined Type compared to ADHD–Predominantly Inattentive, mood disorders, and pervasive developmental disorders.”

The authors sum up their findings for this group of children with subtle disturbances in thyroxine regulation:

“Thyroxine concentrations were associated with mood symptoms and unusual behaviors, and were less strongly related to attentional functioning. Thyroxine concentrations were not related to hyperactivity.”

We can gain additional insight into the issue of thyroid hormone resistance and ADHD from a case report published in the journal Deutsche Medizinische Wochenschrift (German Medical Weekly). The authors state:

“Two siblings with goiter and attention deficit-hyperactivity disorder were presented. Earlier laboratory tests showed increased serum levels of thyroid hormones in association with non-suppressed serum levels of thyrotropin (TSH) in both children.”

Review for lay readers: as in the first paper cited, elevation of thyroid hormones in hyperthyroidism is accompanied by low levels of TSH (thyroid stimulating hormone ‘aka’ thyrotropin, which is  produced in the pituitary; it stimulates thyroid hormone production in the thyroid gland on a feedback loop). Resistance to thyroid hormone by its receptors in the rest of the body can cause TSH to be high even when thyroid hormones are elevated. Peripheral resistance can also cause a low thyroid state with labs that look normal. The doctors in this case did what was necessary to rule out hyperthyroid disease:

“Because hyperthyroidism caused by inappropriate secretion of thyrotropin was suspected, a cerebral MRI was performed. A pituitary adenoma was excluded in both children. Before antithyroid drug treatment was initiated, both patients were referred to our hospital. Careful medical history, clinical examination of the patients and careful interpretation of the laboratory results finally led to the diagnosis resistance to thyroid hormone (RTH).”

This spared the children inappropriate aggressive thyrostatic treatment (thyroid suppression or destruction). Moreover, there are functional therapies for RTH. I certainly concur with the authors’ conclusion:

“Careful medical history, correct interpretation of laboratory results, comprehensive clinical examination and molecular genetic analysis are important in the diagnosis of RTH.”

A paper recently published in the Journal of Affective Disorders sheds more light on how profound thyroid dysregulation evidenced by an increase TSH can be. The authors begin by observing:

“The relationship of bipolar disorder (BD) and altered thyroid function is increasingly recognized. Recently, a behavioral phenotype of co-occurring deviance on the Anxious/Depressed (A/D), Attention Problems (AP), and Aggressive Behavior (AB) syndrome scales has been identified as the Child Behavior Checklist Dysregulation Profile (CBCL-DP), which itself has been linked to BD. This study tested for differences in thyroid function within a sample of psychiatric children and adolescents with and without the CBCL-DP.”

They correlated the CBCL-DP scores according to each behavioral phenotype with serum levels of TSH, fT3 (free T3) and fT4 (free T4). What did their data show?

“In participants showing the CBCL-DP, basal serum TSH was elevated compared to controls. More CBCL-DP subjects than controls showed subclinical hypothyroidism. No differences were observed for serum fT3 and fT4 levels.“

Here again we see the manifestation of resistance to thyroid hormone, this time with elevated TSH and normal fT3 and fT4. It is likely, in our experience, that the chronic microinflammation resulting in peripheral resistance to thyroid hormone (RTH) is due to autoimmune/allergic phenomena that are simultaneously activating microglial cells (immune cells in the brain) to produce neuroinflammation. In this case the brain gets a ‘double whammy’—RTH and brain inflammation.

Bringing the matter even more up to date, an excellent and important paper recently published in the journal Clinical Endocrinology clearly articulates why it is mandatory for clinicians to be alert to functional changes in thyroid hormone measurements that are usually within the ‘normal’ laboratory reference range.The authors stated their initial objective:

“Thyroid hormone concentrations outside the normal range affect brain development, but their specific influence on behaviour and mental abilities within normal values is unknown. The objective of this study was to investigate whether thyroid hormone concentrations are related to neurodevelopment and ADHD (attention deficit and hyperactivity disorder) symptoms in healthy preschoolers.”

They assessed mental and motor development with McCarthy’s scales for neuropsychological outcomes and ADHD-DSM-IV for ADHD symptoms, correlating them with thyroid hormones TSH, free T4 and T3. What did the data show?

“Children with TSH concentrations in the upper quartile of the normal range performed lower on McCarthy’s scales and were at higher risk for attention deficit and hyperactivity/impulsivity symptoms. In the Menorca cohort, a decrease of 5·8 and 6·9 points was observed in memory and quantitative skills, respectively. In contrast, high T4 concentrations were associated with decreased risk of having 1–5 attention deficit symptoms…No associations were observed with T3.”

Bottom line: when there are symptoms of learning, behavioral or developmental disorders, the astute parent or clinician must ask “Is there any indication that thyroid function needs to be investigated in this case?” If so, it must be borne in mind that there are types of thyroid dysfunction that occur in the presence of ‘normal’ values for TSH, T3 and T4. The authors emphasize this in their conclusion:

“Despite being within the normal range, high TSH concentrations are associated with a lower cognitive function and high TSH and low free T4 with ADHD symptoms in healthy preschoolers. Statistically significant differences were observed in the highest quartiles of TSH, suggesting a need for re-evaluation of the upper limit of the normal TSH range.“

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