Suicide and biomarkers of gastrointestinal inflammation

Suicide and gastrointestinal inflammation

Suicide mostly occurs in association with neuropsychiatric disorders characterized by neuroinflammation (brain inflammation). Neuroinflammation often results from perturbations of the brain-gut axis, with pro-inflammatory immune signaling from the gut to the brain. An important study just published in Psychiatry Research offers data showing the connection between biomarkers of gastrointestinal inflammation and recent suicide attempt. The authors were motivated by the intent to validate biomarkers to help assess, treat and prevent suicide attempts.

Most attempting suicide have an illness associated with neuroinflammation

“Psychological autopsy and epidemiological studies indicate that more than 90% of people who die by suicide have a diagnosable psychiatric illness, particularly major depression, bipolar disorder, or schizophrenia…The identification of blood-based markers would provide for more personalized methods for the assessment and treatment, and ultimately prevention, of suicide attempts.”

It is an urgent clinical need to identify causes that promote dysregulated activation of the immune system against the neuronal antigens.

The GI tract is often the source of immune activation against the brain

Biomarkers of gastrointestinal inflammation are frequently increased in neuropsychiatric disorders.

“Many individuals with schizophrenia and mood disorders have evidence of immune activation suggesting that immune dysregulation may be part of the etiopathology of these disorders. Studies by our group and others indicate that the gastrointestinal tract is often the primary source of this immune activation as evidenced by increased levels of markers of gastrointestinal inflammation in individuals with serious mental illness.”

IBD (inflammatory bowel disease) and celiac disease appear to increase risk for suicide.

“Furthermore, increased rates of suicide and suicide attempts have been found in some populations of individuals with celiac disease or inflammatory bowel diseases.”

But previous studies have focused on a lifetime history rather than attempts, so the authors set out to:

“…examine the association between levels of markers of gastrointestinal inflammation and a recent suicide attempt in individuals with schizophrenia, bipolar disorder or major depressive disorder in comparison with non-psychiatric controls.”

Elevated IL-6

Interleukin-6 (IL-6), a key pro-inflammatory cytokine which can arise from the GI tract, is associated.

“Results from other investigators indicate that inflammation may be associated not only with a proclivity for a psychiatric disorder, but specifically with suicidal behavior. Studies have found an association between a suicide attempt history and the level of cytokines such as IL-6 which are cell signaling molecules involved in the immune response and which can arise from inflammation from many sources, including the gastrointestinal tract”

Gluten and brain inflammation

Neuroinflammation triggered by non-celiac gluten sensitivity is also implicated:

“Gliadin is a component of gluten, found in wheat and related cereals. Antibody response to dietary gliadin is associated with celiac disease, an immune-mediated enteropathy, and with non-celiac wheat sensitivity and is thought to indicate intestinal inflammation and/or intestinal barrier dysfunction. We have found increased levels of antibodies to gliadin in individuals with schizophrenia and with bipolar disorder and in individuals with acute mania during a hospital stay…”

Additionally, loss of tolerance to a commensal yeast may promote neuroinflammation.

“We also have studied the antibody response to yeast mannans represented by antibodies to Saccharomyces cerevisiae (ASCA), a commensal organism present in some foods and in the intestinal tract of many individuals. Elevated ASCA levels are associated with increased intestinal inflammation. We have previously found increased levels of ASCA in individuals with mood disorders.”

Pathogens and loss of immune tolerance

Various pathogens present at low levels can elicit a persistent cross-reaction to self-antigens, including brain antigens, in individuals disposed to loss of immune tolerance.

“An association between elevated antibodies to Toxoplasma gondii, an apicomplexan parasite, and suicide attempts have also been reported. In a recent study, we found that individuals with serious mental illness who had a lifetime history of a suicide attempt had elevated levels of IgM class antibodies to Toxoplasma gondii and Cytomegalovirus (CMV); we also found an association between the levels of these antibodies and the number of suicide attempts.”

Significant link found

Association between suicide and markers of GI inflammation

The authors examined data for 282 participants: 90 with schizophrenia, 72 with bipolar disorder, 48 with major depressive disorder, and 72 non-psychiatric controls; who were enrolled in ongoing studies of the role the immune response to infections in individuals with serious psychiatric disorders. Biomarkers measured included IgA antibody to yeast mannan from Saccharomyces cerevisiae (ASCA), IgG antibody to gliadin, IgA antibody to bacterial lipopolysaccharide (LPS) from E. coli O111:B4, Pseudomonas aeruginosa, and Klebsiella pneumoniae, and levels of C-Reactive protein.

“We found a statistically significant difference between the recent attempters and the control group in levels of IgA ASCA; the level in the recent attempt group was significantly higher…We also found that the level of IgG antibodies to gliadin was significantly higher in the recent attempters vs. the control group…We also found that the level of IgA antibodies to bacterial lipopolysaccharide (LPS) was significantly higher in the recent attempters vs. the control group…In terms of CRP, we found that there was a significantly higher level in the past attempter group.”

Predicting risk and protecting patients

These findings offer a valuable opportunity for clinicians to gauge and ameliorate risk of suicide in patients with serious neuropsychiatric disorders.

“The markers of gastrointestinal inflammation are of interest because they can be readily measured in blood samples. In addition, some of the markers studied here may be an attractive target for therapeutic intervention since intestinal inflammation can be modulated by dietary interventions as well as the administration of available prebiotic, probiotic, and antibiotic medications.”

The authors conclude:

“Suicide, for which a previous suicide attempt is the greatest risk factor, is a major cause of death worldwide and is highly prevalent in patients with serious mental illness. Unfortunately, the ability to predict suicide remains limited and no reliable biological markers are available. The identification of blood-based markers should provide for more personalized methods for the assessment and treatment, and ultimately prevention, of suicide attempts in individuals with serious mental illnesses.”

For additional categories of importance in evaluating neuropsychiatric risk see The Parents’ Guide to Brain Health.

Eating disorders and the causative role of autoimmunity

PLOS ONEEating disorders are multifactorial; like other psychiatric conditions the causative role of auotimmune neuroinflammation is coming to the fore as evidenced by a study just published in PLoS One (Public Library of Science). The authors note regarding earlier reports relevant to autoimmunity in eating disorders:

“A prior autoimmune disease has recently been shown to increase the risk of mood disorders and schizophrenia. In addition, the risk of both mental disorders increased in a dose response pattern when autoimmune diseases and infections were assessed together. The role of autoimmune processes, such as various pathogens triggering autoantibodies cross-reactive with neuronal antigens (brain-reactive autoantibodies), has also been recognized in the pathogenesis of neuropsychiatric disordersincluding autism spectrum disorders, obsessive-compulsive disorder, tic-disorders, ADHD, post-traumatic stress disorder, and narcolepsy. Furthermore, pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal infection (PANDAS) include anorexia nervosa (AN).”

Research suggests autoimmune processes to be involved in psychiatric disorders. We aimed to address the prevalence and incidence of autoimmune diseases in a large Finnish patient cohort with anorexia nervosa, bulimia nervosa, and binge eating disorder.”

Moreover…

Crohn’s disease and celiac disease have been suggested to act as triggers for the development of eating pathology, and individuals with celiac disease are reported to be at increased risk for eating disorders…To our knowledge, no large scale reports of the co-morbidity of autoimmune diseases and eating disorders have been published. 

So they compared 2342 patients with eating disorders compared to 9368 matched controls from the general population and correlated that with data for 30 autoimmune diseases and found a pertinent association:

“Of patients, 8.9% vs. 5.4% of control individuals had been diagnosed with one or more autoimmune disease. The increase in endocrinological diseases was explained by type 1 diabetes, whereas Crohn’s disease contributed most to the risk of gastroenterological diseases. Higher prevalence of autoimmune diseases among patients with eating disorders was not exclusively due to endocrinological and gastroenterological diseases; when the two categories were excluded, the increase in prevalence was seen in the patients both before the onset of the eating disorder treatment and at the end of the follow-up.”

Shared immunological mechanisms

In other words, the crucial point is that there are shared immunological mechanisms:

“We observed an increased risk for several autoimmune diseases among patients with eating disorders supporting the hypothesis of co-morbidity of these disorders and suggesting that immune-mediated mechanisms could play a role in the development of eating disorders. Importantly, our results were not restricted to the association of T1D with eating disorders as shown in previous studies. Instead, the association was seen for several autoimmune diseases with different genetic backgrounds. Our findings thus suggest that the link between eating disorders and autoimmune diseases is based on shared immunological mechanisms, rather than on the shared genetic background, e.g. the shared HLA risk genotype. In addition, our findings support earlier observations suggesting that autoimmune processes contribute to the onset and maintenance of eating disorders, at least in a subpopulation of patients.”

Chronic inflammation in psychiatric disorders

Chronic inflammation must be assessed in psychiatric disorders:

“Studies indicate that psychiatric disorders co-exist with inflammation, infections and autoimmune diseases, and shared vulnerability underlying many psychiatric disorders suggest that findings from one disorder may be relevant across categories. Pro-inflammatory cytokines and antibodies/autoantibodies against neuronal antigens could induce changes in neurotransmitter and neuroendocrine function, which may subsequently yield psychiatric manifestations. Studies suggest that pro-inflammatory cytokines may have a role in eating disorders.”

Pro-inflammatory cytokines

A key clinical point for clinicians, especially those of us who assess serum cytokines, is the fact that they may be elevated in the brain while remaining normal in the blood:

“It has also been suggested that pro-inflammatory cytokines might be overproduced in specific brain areas and act locally without concomitant increase in serum or immune production. Indeed, the pro-inflammatory cytokines are able to activate HPA axis, the hyperactivity of which in eating disorders has been established.”

Gut-brain axis

Regarding the role of the gut-brain axis and autoimmunity:

“Our findings are supported by the immunological studies performed in patients with eating disorders, where autoantibodies against peptides related to appetite-regulation, stress response, and social-emotional functioning (α-MSH, ACTH, ghrelin, oxytocin, vasopressin) were detected. The postulated role of intestinal microflora contributing to the development of cross-reactive neuronal autoantibodies provides a link between gut and brain…Gut microbiota is an important regulator of the immune system and its alteration has been associated with autoimmune diseases and immune-mediated disorders, such as allergies and T1D. Composition of the microbiota affects gut permeability, and the function of both innate and adaptive immune system including development of regulatory T-cells.”

Sex hormones

Practitioners must also bear in mind that sex hormone dysregulation, as noted earlier here, can contribute to loss of immune tolerance:

“…sex hormones modulate microbiota and the development of autoimmunity, as well as the eating disorders risk. The interplay between gut microbiome, immune regulation, and sex hormones thus provide one potential, complex mechanism underlying eating disorders and explaining the partly shared etiopathogenesis of eating disorders and autoimmune diseases.”

Medscape Medical News quotes the lead author:

“I was surprised about the robust link that we found between autoimmune diseases and eating disorders,” lead author Anu Raevuori, MD, PhD, from the Department of Public Health at the University of Helsinki, Finland.

“On the other hand, my clinical impression is that in many patients with eating disorders, particularly those with long-lasting and persistent symptoms, the disorder appears to have a biological background,” said Dr. Raevuori.

“…other lines of research suggest that some of those eating disorder patients that do not have a diagnosable autoimmune disease might have underlying autoimmunological factors, such as autoantibodies against peptides…related to appetite regulation, stress response, and social-emotional functioning, which could explain their symptoms.”

Anyone involved in case management for patients suffering from eating disorders should consider the authors’ summation:

“In conclusion, we observed the association between eating disorders and several autoimmune diseases with different genetic backgrounds. Our data support the findings from other studies indicating the role of immunological mechanisms at least in a subpopulation of patients with eating disorders. We recommend that clinicians treating patients with eating disorders consider the increased risk of autoimmune diseases and the possible role of autoimmune processes underlying these individuals’ somatic and neuropsychiatric symptoms related to mood disturbances, anxiety and disordered eating.”

Schizophrenia risk increased by maternal inflammation

American Journal of PsychiatrySchizophrenia is well recognized to have a neuroinflammatory component, and a study just published in the American Journal of Psychiatry links maternal inflammation during pregnancy as reflected in elevated CRP (C-reactive protein) levels with a markedly increased irisk of schizophrenia in offspring. The authors state:

“The objective of the present study was to investigate an association between early gestational C-reactive protein, an established inflammatory biomarker, prospectively assayed in maternal sera, and schizophrenia in a large, national birth cohort with an extensive serum biobank.”

They examined the maternal sera of 777 schizophrenia cases for C-reactive protein in comparison to 777 matched control subjects. The correlation was striking:

“Increasing maternal C-reactive protein levelswere significantly associated with schizophrenia in offspring. This finding remained significant after adjusting for potential confounders, including maternal and parental history of psychiatric disorders, twin/singleton birth, urbanicity, province of birth, and maternal socioeconomic status.”

A reviewer in Medscape Family Medicine notes:

“A growing body of epidemiologic and preclinical evidence suggests that infection and subsequent immune activation play a role in the etiology of schizophrenia, the researchers note.”

Also noted in Medscape Family Medicine:

  • “Overall, the median maternal C-reactive protein level for case patients was 2.47 mg/L. The median level for control individuals was 2.17 mg/L.
  • The investigators found that for every 1 mg/L increase in maternal C-reactive protein, the risk for schizophrenia was increased by 28%.
  • The investigators speculate that “maternal inflammation during pregnancy may ‘prime’ the brain to broadly increase the risk for the later development of different types of psychiatric syndromes.”
  • They note that their previous research in this same Finnish national birth cohort “demonstrated a significant increase in maternal C-reactive protein levels in pregnancies that gave rise to childhood autism.”

Authors of an accompanying editorial note:

“Firstly, while the authors only assessed C-reactive protein, proinflammatory markers, such as interleukin 8 and tumor necrosis factor alpha, have been shown to have similar associations in other birth cohorts. This suggests that the risk is associated with a generally elevated inflammatory state. Secondly, the inflammation story does not appear to be specific to schizophrenia because elevated markers of inflammation are also found in association with depression, with posttraumatic stress disorder, and in many physical diseases Indeed, Brown and his research group have also reported elevated levels of maternal C-reactive protein in association with autism…The inflammatory system and the hypothalamic-pituitary-adrenal (HPA) axis, which mediates the stress response, are inextricably linked: cytokines can elicit a stress response through activation of the fetal HPA axis, and stressors can lead to HPA axis dysregulation and loss of normal glucocorticoid-associated anti-inflammatory tone. Cotter and Pariante previously proposed that many of the neuropathological features observed in schizophrenia are in keeping with nonspecific glucocorticoid-related brain changes. Autoimmunity may also underlie some of the elevation in inflammatory tone seen in people with schizophrenia, and a bidirectional association between schizophrenia and autoimmune disorders has been reported. The recent upsurge of interest in anti-N-methyl-d-aspartic acid receptor encephalitis as a differential diagnosis for schizophrenia demonstrates the importance of autoimmunity in psychosis.”

The authors of the primary paper conclude:

“This finding provides the most robust evidence to date that maternal inflammation may play a significant role in schizophrenia, with possible implications for identifying preventive strategies and pathogenic mechanisms in schizophrenia and other neurodevelopmental disorders.”

Infection and Autoimmunity

BMJ Open Clinicians who undertake case management of autoimmunity that latent autoimmune conditions are often triggered by for which there are scores of examples. In this context it’s edifying to consider another just-published study in BMJ (British Medical Journal) Open examining infection as a trigger for rheumatoid arthritis:

“We observed a marked increase in overall infections at the time of RA onset, and signs of a defective antibacterial defence mechanism, contrasting with fewer infections in the late RA stage…The model is supported by evidence indicating that monocytes and macrophages as well as other cytokine-producing cell types, are key players in RA, and by more recent reports of non-specific and sustained immunostimulation during RA development…It can be speculated that frequent early infections initiate a compensatory immune hyper-reactivity which reduces the infection load while stimulating the development of RA in predisposed individuals.”

Clinical note: “…in predisposed individuals” is a critical point. Practitioners should be adept in comprehensively assessing the various potential underlying contributing causes that predispose to loss of immune tolerance.

Depression and brain inflammation

JAMAEvidence for the role of brain inflammation in depression is proliferating as noted in a report published recently in JAMA (Journal of the American Medical Association):

Activation of the immune system is the body’s natural reaction to infection or tissue damage, but when this protective response is prolonged or excessive, it can play a role in many chronic illnesses, not only of the body, but also of the brain...Psychiatric and neurodevelopmental disorders are being thought of more and more as systemic illnesses in which inflammation is involved,” noted Eric Hollander, MD, of Montefiore Medical Center and Albert Einstein College of Medicine, New York City.

Certain biomarkers including the proinflammatory cytokines interleukin-6 (IL-6) and TNF, and CRP are standing out in depression:

“…early studies showing that patients with depression, regardless of their physical health status, exhibited cardinal features of inflammation, including increases in inflammatory cytokines in the blood and cerebrospinal fluid.”

 IL-6 and CRP In Neuropsychiatric Disorders

JAMA PsychiatryAlong these lines, a study just published in JAMA Psychiatry shows that higher levels of the proinflammatory cytokine IL-6 and the inflammatory biomarker CRP (C-reactive protein) are associated with depression in childhood and psychosis in young adulthood. Noting that…

Recent meta-analyses of cross-sectional studies have reported increased serum levels of these inflammatory markers in depression, first-episode psychosis, and acute psychotic relapse; however, the direction of the association has been unclear“…

The authors determined to…

“..test the hypothesis that higher serum levels of IL-6 and CRP in childhood would increase future risks for depression and psychosis.”

To do so they measured levels of IL-6 and CRP in 4500 individuals at age 9 years, then assessed them at age 18 years for depression using the Clinical Interview Schedule–Revised (CIS-R) and Mood and Feelings Questionnaire (MFQ); and psychotic experiences (PEs) and psychotic disorder by semistructured interviews. Their data were particularly striking for IL-6 in depression and psychosis:

“After adjusting for sex, age, body mass index, ethnicity, social class, past psychological and behavioral problems, and maternal postpartum depression, participants in the top third of IL-6 values compared with the bottom third at age 9 years were more likely to be depressed (CIS-R) at age 18 years (adjusted odds ratio [OR], 1.55). Results using the MFQ were similar. Risks of PEs and of psychotic disorder at age 18 years were also increased with higher IL-6 levels at baseline (adjusted OR, 1.81). Higher IL-6 levels in childhood were associated with subsequent risks of depression and PEs in a dose-dependent manner.”

IL-6 proved to be a more robust biomarker than CRP as there was no association of childhood CRP levels and psychiatric illness at age 18, while IL-6 was a good predictor. The authors conclude:

Higher levels of the systemic inflammatory marker IL-6 in childhood are associated with an increased risk of developing depression and psychosis in young adulthood. Inflammatory pathways may provide important new intervention and prevention targets for these disorders. Inflammation might explain the high comorbidity between heart disease, diabetes mellitus, depression, and schizophrenia.

Inflammation and Antidepressants

American Journal of PsychiatryThe authors of a study recently published in the American Journal of Psychiatry report that levels of CRP predicted the response to a SSRI (escitalopram/Lexapro®) versus nortryptipline (tricyclic antidepressant that is primarily a norepinephrine reuptake inhibitor):

Major depressive disorder has been linked with inflammatory processes, but it is unclear whether individual differences in levels of inflammatory biomarkers could help match patients to treatments that are most likely to be beneficial. The authors tested the hypothesis that C-reactive protein (CRP), a commonly available marker of systemic inflammation, predicts differential response to escitalopram (a serotonin reuptake inhibitor) and nortriptyline (a norepinephrine reuptake inhibitor).”

They measured CRP in 241 adult men and women with major depressive disorder who were randomly allocated to 12 weeks of treatment with Lexapro® or nortriptyline and rated their response weekly with the Montgomery-Åsberg Depression Rating Scale (MADRS). CRP levels were indeed able to predict the response:

CRP level at baseline differentially predicted treatment outcome with the two antidepressants (CRP-drug interaction: β=3.27, 95% CI=1.65, 4.89). For patients with low levels of CRP (<1 mg/L), improvement on the MADRS score was 3 points higher with escitalopram than with nortriptyline. For patients with higher CRP levels, improvement on the MADRS score was 3 points higher with nortriptyline than with escitalopram. CRP and its interaction with medication explained more than 10% of individual-level variance in treatment outcome.”

These data lead the authors to conclude:

“An easily accessible peripheral blood biomarker may contribute to improvement in outcomes of major depressive disorder by personalizing treatment choice.”

So inflammation impaired the response to the SSRI Lexapro®. Patients with higher levels of inflammation did better with nortryptiline, but why?

Norepinephrine reduces  brain oinflammation

PNASA fascinating study published in PNAS (Proceedings of the National Academy of Sciences) sheds light on this by demonstrating that norepinephrine (the levels of which are raised by nortryptiline, a norepinephrine reuptake inhibitor), acts as an antiinflammatory agent in the brain. The authors observed this in the course of investigating the role of norepinephrine in promoting brain inflammation that clears the amyloid beta (Aβ) associated with Alzheimer’s disease:

Locus ceruleus (LC)-supplied norepinephrine (NE) suppresses neuroinflammation in the brain. To elucidate the effect of LC degeneration and subsequent NE deficiency on Alzheimer’s disease pathology, we evaluated NE effects on microglial key functions. NE stimulation of mouse microglia suppressed Aβ-induced cytokine and chemokine production and increased microglial migration and phagocytosis of Aβ… In vivo laser microscopy confirmed a Aβ deposition in response to noradrenergic depletionreduced recruitment of microglia to Aβ plaque sites and impaired microglial Aβ phagocytosis in NE-depleted APP-transgenic mice. Supplying the mice the norepinephrine precursor L-threo-DOPS restored microglial functions in NE-depleted mice. This indicates that decrease of NE in locus ceruleus projection areas facilitates the inflammatory reaction of microglial cells in AD and impairs microglial migration and phagocytosis, thereby contributing to reduced Aβ clearance. Consequently, therapies targeting microglial phagocytosis should be tested under NE depletion.”

In other words, inflammation went up as norepinephrine went down. This informs us that well-regulated inflammation is an important housekeeping function of the brain’s glial cells, but also reveals the link between the relief of depression due dysregulated inflammation when suppressed by norepinephrine.

Clinical note: no analysis and treatment plan for depression is complete without investigating for neuroinflammation and its causes, for which there are numerous sustainable interventions.

Neuropsychiatric illness in non-celiac gluten sensitivity

Gastroenterology Research and PracticeNeuropsychiatric illness can result from neuroinflammation due to a variety of causes. Recent studies offer more evidence that depression and other neuropsychiatric disorders can be a manifestation of non-celiac gluten sensitivity. A paper published in Gastroenterology Research and Practice explores the pathophysiologic mechanisms by which gluten sensitivity can present as a variety of neuropsychiatric conditions in the absence of celiac disease. The authors note:

“…emerging scientific literature has noted a link between gluten ingestion and symptomatology from nearly every organ system, often in the absence of classic histological findings of CD on intestinal biopsy…It has been hypothesized for quite some time that gluten sensitivity may also impair central nervous system functioning. In 1996, Hadjivassiliou et al. found a significant difference in the prevalence of patients with positive antigliadin antibodies amongst those with neurological symptoms of unknown cause (57%) compared to a control group of healthy patients (12%). Amid the 57% who did have positive antibody titres, the majority did not demonstrate histological evidence diagnostic of celiac disease. In a 2010 article published in Lancet Neurology, Hadjivassiliou and colleagues published additional support for the link between gluten sensitivity and neurological manifestations, including ataxia, neuropathy, encephalopathy, epilepsy, myopathy, and myelopathy. Similar results continue to be reported in the medical literature and give credence to the association between gluten sensitivity and neurological symptoms in the absence of celiac disease.”

They present an illustrative case of a 23-year-old woman with a longstanding history of auditory and visual hallucinations that completely resolved by avoiding gluten, and would recur when provoked by a gluten exposure. The authors state:

“There have been multiple reports linking celiac disease and/or gluten sensitivity with mental health manifestations including isolated psychosis and full blown schizophrenia. As in our case history, these cases report complete symptom resolution with removal of gluten. There is also evidence of frequent gluten sensitivity (but not celiac disease) in schizophrenic patients. Furthermore, similar reports are published dealing with various other neurological manifestations in response to gluten exposure including “idiopathic” ataxia and neuropathies, epilepsy, mood swings, and autism. In addition to neuropsychiatric phenomena, there are reports of other organ system involvement including reversible cardiomyopathy, resolved primary infertility, uveitis, and osteoporosis in relation to the gluten exposure in celiac disease.”

Regarding causation in autoimmunity or sensitivity related illness (SRI), the authors discuss a topic of premiere clinical importance: toxicant induced loss of tolerance (TILT):

“This mechanism of disease has recently been described and discussed in the scientific literature, whereby accumulated toxic insults often resulting from adverse chemical exposures lead to hypersensitivity and impaired tolerance of the immune system (known as toxicant induced loss of tolerance or “TILT”). With growing attention in the medical literature to the escalating problem of toxicant exposure and bioaccumulation within contemporary society, this mechanism of illness has become compelling indeed. Notable groups such as the World Health Organization and the Centers for Disease Control have recently drawn attention to the reality of ubiquitous toxicant exposures and the chemical erosion of human health associated with toxicant accrual within the human body.”

Sensitivity related illness- a causative pathway to multimorbidityAs for TILT in gluten-induced neuropsychiatric disease:

After the bioaccumulation of a toxicant burden and the consequent immune dysregulation, seemingly insignificant environmental triggers can lead to the release of proinflammatory cytokines, antibodies, chemokines, and interleukins and produce a variety of symptoms, including neuropsychiatric issues, in the affected patient. Gluten is one such common trigger, and is hypothesized to be the culprit in the above case report. With the ability of SRI to induce multisystem manifestations and with its increasing and widespread prevalence, this mechanism of disease is the preferred explanation of the authors for gluten-induced neuropsychiatric disease…This mechanism also explains the apparently inexplicable onset of gluten sensitivity in patients who were previously well and fully tolerant of gluten and accounts for the reversal of gluten sensitivity in some patients who are successful in eliminating their toxicant burden.”

Commenting in conclusion on their case presentation:

“The individual in the presented case demonstrates a clear sensitivity to gluten with remission of longstanding hallucinations with gluten elimination and relapsing symptoms upon reintroduction of dietary gluten. The scientific literature contains numerous case reports where unexplained symptoms are significantly improved and, at times, completely resolved when similar dietary changes are made. Therefore, when clinicians are faced with physical symptoms that have not been otherwise explained, celiac testing may be warranted. If this is found to be negative, the possibility of NCGS and SRI ought to be considered. Although NCGS cannot be definitively diagnosed at this time based on laboratory investigations, a trial of gluten elimination should be incorporated as part of the clinical assessment and potential management.”

Clinical note: non-celiac gluten sensitivity (NCGS) can now be assessed with the Wheat/Gluten Proteome Reactivity & Autoimmunity panel from Cyrex Laboratories and correlated with their Multiple Autoimmune Reactivity Screen that includes anti-brain antibodies.

The authors summarize their key points:

  1. Gluten ingestion in gluten sensitive individuals can lead to a variety of clinical presentations including psychiatric, neurological, gynecological, and cardiac symptoms.
  2. Dietary elimination of gluten may lead to complete symptom resolution.
  3. Health practitioners are advised to consider gluten elimination in patients with otherwise unexplained symptoms.
  4. Non-celiac gluten sensitivity may be a part of a constellation of symptoms resulting from a toxicant induced loss of tolerance (TILT).

 Depression In Non-Celiac Gluten Sensitivity

Alimentary Pharmacology & TherapeuticsA recent clinical trial investigating depression in non-celiac gluten sensitivity was recently published in Alimentary Pharmacology and Therapeutics that demonstrated depression in the absence of gastrointestinal symptoms. The authors state:

“Current evidence suggests that many patients with self-reported non-coeliac gluten sensitivity (NCGS) retain gastrointestinal symptoms on a gluten-free diet (GFD) but continue to restrict gluten as they report ‘feeling better’.”

So they set out to discriminate between mental and gastrointestinal symptoms in NCGS by a double-blind cross-over study in which their subjects received one of three dietary challenges for 3 days, followed by a minimum 3-day washout before crossing over to the next diet ( the challenge gluten-free food was supplemented with gluten, whey (16 g/day) or not supplemented = placebo. Depression scores as assessed by the Spielberger State Trait Personality Inventory (STPI) stood out in association with gluten exposure:

Gluten ingestion was associated with higher overall STPI state depression scores compared to placebo but not whey. No differences were found for other STPI state indices or for any STPI trait measures. No difference in cortisol secretion was identified between challenges. Gastrointestinal symptoms were induced similarly across all dietary challenges.”

Clinical note: In gluten intolerance there is often cross-reactivity to bovine dairy proteins due to similarities in antigen morphology.

The authors conclude:

Short-term exposure to gluten specifically induced current feelings of depression with no effect on other indices or on emotional disposition. Gluten-specific induction of gastrointestinal symptoms was not identified. Such findings might explain why patients with non-coeliac gluten sensitivity feel better on a gluten-free diet despite the continuation of gastrointestinal symptoms.”

Clinical note: Practitioners should bear in mind that FODMAP (Fermentable Oligo-Di-Monosaccharides and Polyols) intolerance can coexist with non-celiac gluten sensitivity wherein the former produces gastrointestinal symptoms while the latter accounts for depression and other neuropsychiatric illness.

Bipolar disorder and neuroinflammation

Journal of NeuroinflammationBipolar disorder, like a host of other psychiatric illnesses, should be assessed for neuroinflammation and its underlying causes as evidenced by a wealth of recently published studies. The authors of a paper recently published in the Journal of Neuroinflammation state:

“Multiple lines of evidence support the pathogenic role of neuroinflammation in psychiatric illness. While systemic autoimmune diseases are well-documented causes of neuropsychiatric disorders, synaptic autoimmune encephalitides with psychotic symptoms often go under-recognized. Parallel to the link between psychiatric symptoms and autoimmunity in autoimmune diseases, neuroimmunological abnormalities occur in classical psychiatric disorders (for example, major depressive, bipolar, schizophrenia, and obsessive-compulsive disorders).”

Or great practical clinical significance…

“As biological abnormalities are increasingly identified among patients with psychiatric disorders, the distinction between neurological and psychiatric illness fades. In addition to systemic autoimmune diseases associated with psychiatric manifestations (for example, lupus), more recently, patients with acute isolated psychosis were identified with synaptic autoimmune encephalitides. These patients are often erroneously diagnosed with refractory primary psychotic disorders, delaying initiation of effective immune therapy. Additionally, growing evidence supports the pathogenic role of anti-neuronal antibodies in neuropsychiatric disorders.”

The authors undertake a review of the extensive literature documenting the role of common autoimmune disorders, autoimmune encephalitides associated with serum anti-synaptic and glutamic acid decarboxylase autoantibodies, anti-basal ganglia/thalamic autoantibodies, and innate inflammation with glial pathology, elevated cytokines levels, cyclooxygenase activation, glutamate dysregulation, increased S100B levels, increased oxidative stress, and blood brain barrier (BBB) dysfunction in bipolar disorder and other neuropsychiatric illnesses.

Regarding the use of antiinflammatory agents in the treatment of psychiatric disorders they state:

“Several human and animal studies suggest that certain antiinflammatory drugs may play an important adjunctive role in the treatment of psychiatric disorders…Although current immune therapies (for example, IVIG, plasmapheresis, corticosteroids and immunosuppressive agents) are often effective for treating autoimmune encephalitides wherein inflammation is acute, intense and predominately of adaptive origin, their efficacy in classical psychiatric disorders wherein inflammation is chronic, much milder, and predominately of innate origin, is limited. Development of novel therapeutics should aim at reversing glial loss, down-regulating harmful MAP [microglial activation and proliferation], while optimizing endogenous neuroprotective T regs and beneficial MAP, rather than indiscriminately suppressing inflammation as occurs with current immunosuppressive agents. Additionally, development of potent co-adjuvant antioxidants that would reverse oxidative injury in psychiatric disorders is needed.”

 

Current Psychiatry ReportsIn reference to bipolar disorder specifically the authors of a paper published in Current Psychiatry Reports state:

Bipolar disorder is now known to be associated not only with highly prevalent co-occurring psychiatric and substance use disorders but also with medical comorbidities, such as cardiovascular diseases, diabetes mellitus, obesity and thyroid dysfunction. Inflammatory disturbances repeatedly observed in bipolar disorder, can explain some of the comorbidity between bipolar disorder and medical disorder. This revised perspective of bipolar disorders should promote the development of therapeutic tools.”

In particular…

Immuno-inflammatory dysfunction may well represent a significant component of the underlying pathophysiology of the disorder. We therefore propose to review the immuno-inflammatory hypothesis in bipolar disorder considering the co-occurence with autoimmune diseases, immunological and inflammatory markers, as well as immuno-genetic markers which could lead to personalized treatments.”

 

Australian & New Zealand Journal of PsychiatryA recent paper in the Australian & New Zealand Journal of Psychiatry strikes a similar chord and highlights the role of autoimmunity:

“Increasing evidence suggests that inflammation and immune dysregulation play an important role in the pathogenesis of bipolar disorder. Because the brain can be affected by various autoimmune processes, it is possible that some psychiatric disorders may have an autoimmune basis.”

In review of the literature on peripheral and central immune dysregulation and autoimmunity in bipolar disorder they note, in addition to the mechanisms described above, association with common autoimmune conditions such as SLE and autoimmune thyroiditis:

Neuroinflammation and peripheral immune dysregulation may play a role in the pathophysiology of bipolar disorder. This involves a complex interaction between immune cells of the central nervous system and periphery resulting in cellular damage through mechanisms involving excitotoxicity, oxidative stress, and mitochondrial dysfunction. Neuropsychiatric systemic lupus erythematosus, anti-NMDA encephalitis, and Hashimoto’s encephalopathy are important differentials for a psychiatrist to consider when suspecting autoimmune encephalopathy.”

The authors conclude:

The link between immune dysregulation, autoimmunity, and bipolar disorder may be closer than previously thought. Psychiatrists should be vigilant for autoimmunity in presentations of bipolar disorder due to its high morbidity and therapeutic implications. Advances in neuroimaging and biomarker identification related to immune dysregulation and neuroinflammation will contribute to our knowledge of the pathophysiology of bipolar disorder.”

 

Journal of Affective DisordersIn a paper published in the Journal of Affective Disorders, the authors examine the incidence of comorbid medical disorders and present evidence that…

“…bipolar disorder can be effectively conceptualized as a multi-systemic inflammatory disease.”

They dispense with the notion that comorbid medical disorders are entirely due to the deleterious effects of psychotropic medications:

“Until recently, a lot of emphasis has been put on the fact that psychotropic medication contributes to cardiovascular risk factors. Lithium can cause weight gain and adversely influence glucose metabolism, valproic acid is associated to weight gain and insulin resistance, second generation anti-psychotics are associated to hyperlipidemia, increased risk with diabetes, and weight gain though the extent of weight gain depends on which antipsychotic is used. It should however be stressed that the increased mortality rate in bipolar predate modern pharmacologic treatments. In addition, the fact that the association between cardiovascular risk factors and bipolar disorder remains significant after controlling for these co-factors strongly suggests that mechanisms specific to bipolar disorder itself have yet to be identified.”

And in fact inflammation is common to both:

“Inflammation has been shown to be crucial throughout atherosclerosis from endothelial dysfunction to plaque rupture and thrombosis; a number of studies also suggest that inflammation may be implicated in the pathophysiology of bipolar disorder (for review see, Goldstein et al., 2009). The data supporting the hypothesis that inflammation could be a common factor underlying both cardio-vascular and bipolar disorder is important to be reviewed.”

Bipolar disorder and abnormal immuno-inflammationMoreover…

“Over the last two decades, it has been shown that inflammatory processes and neural immune interactions are involved in the pathophysiology of major depression, these data also shed light on how to explain the plausible link between increased levels of cytokines and mood states in bipolar disorder. A pro-inflammatory state is known to activate the tryptophan and serotonin-degrading-enzyme, indoleamine 2–3 dioxygenase (IDO), which has been found elevated in the plasma of bipolar patients. Activation of this enzyme leads to increased consumption of tryptophan, thus reducing the availability of serotonergic neurotransmission, as well as inducing the production of detrimental tryptophan catabolites with neurotoxic effects. It has also been shown that the activity of dopaminergic system is reduced in response to inflammation while cytokines enhance the re-uptake of monoamine neuro-transmitters thereby reducing their intra-synaptic concentrations in the brain.”

BDNF (brain derived neurotrophic factor) regulation is also disrupted:

“The pro-inflammatory cytokines also induce decrease in neurotrophins, and in particular diminished levels of Brain-Derived-Neurotrophic-Factor (BDNF) leading to decrease neuronal repair, decrease in neurogenesis and an increased activation in glutamatergic pathway which also contributes to neuronal apoptosis. It is noteworthy that serum BDNF has been associated both with changes in mood states in bipolar disorder as well as in coronary heart diseases.”

The autoimmune component is of premiere importance:

“A relationship between auto-immune disorders and bipolar disorder has been reported as early as 1888. Patients with bipolar disorder tend to develop organ-specific autoimmunity as shown, for example, by thyro-peroxidase antibodies (TPO-Abs) associated with thyroid failure, by antibodies to H/KAT-Pase associated with atrophic gastritis and by GAD65A, isoform of glutamic acid decarboxylase which is a marker of type-I diabetes. Recently, manic episodes with psychotic symptoms were observed during acute encephalitis with antibodies directed in particular against extracellular domains of the glutamatergic NMDA receptor. In addition, it has recently been reported that gastrointestinal processing of food antigens such as bovine caseins and wheat glutens is altered in bipolar disorder. Bipolar patients have been reported to have increased antibodies to gliadin, a glycoprotein derived from the ingestion of gluten from wheat or to casein activation, particularly during mania…Presence of these auto-antibodies might even precede the onset of bipolar disorder, as an increased prevalence of Multiple Sclerosis, thyrotoxicosis, ulcerative colitis, psoriasis and rheumatoid arthritis has been reported in unaffected relatives of patients with BD.”

 

Current Opinion in PsychiatryThe authors of a paper just published in Current Opinion in Psychiatry note:

“Recent studies have shown that bipolar disorder involves microglial activation and alterations in peripheral cytokines and have pointed to the efficacy of adjunctive anti-inflammatory therapies in bipolar depression.”

They summarize their findings by stating:

“The presence of active microglia and increased proinflammatory cytokines in bipolar disorder suggests an important role of inflammatory components in the pathophysiology of the disease, as well as a possible link between neuroinflammation and peripheral toxicity.”

 

Biological PsychiatryInflammatory microglial activation due to a dysregulated immune system is identified as a key factor in psychosis of all types in a paper just published in Biological Psychiatry:

“Accumulating evidence supports the view that deregulation of the immune system represents an important vulnerability factor for psychosis. In a subgroup of psychotic patients, the high comorbidity with autoimmune and chronic inflammatory conditions suggests a common underlying immune abnormality leading to both conditions.”

Microglia are the immune cells of the brain, functioning as macrophages do in peripheral tissues…

“Indeed, there is some evidence of activation of the microglia as detected in positron emission tomography scans and in histopathology, and it is assumed that this activation disturbs the development and function of neuronal circuits in the brain. Further, animal models of psychotic conditions (maternal stress and inflammation paradigms) suggest that such monocyte/microglia activation could be seen as the result of a combination of genetic predisposition and an immune-mediated two-hit model.”

The ‘two-hit’ model features strongly in a multitude of immune and other disorders:

“Infection but also environmental stressors during gestation/early life activate microglia, perturbing neuronal development, thereby setting the stage for vulnerability for later psychotic disorders. A second hit, such as endocrine changes, stress, or infection, could further activate microglia, leading to functional abnormalities of the neuronal circuitry in the brain and psychosis.”

 

Journal of Affective DisordersA study also published recently in the Journal of Affective Disorders highlights C-reactive protein (CRP) as an inflammatory marker in bipolar disorder. The authors note:

“Some individuals with bipolar disorder have cognitive deficits even when euthymic. In previous studies, we found an association between elevated levels of C-reactive protein (CRP), a marker of inflammation, and reduced cognitive functioning in schizophrenia. This issue has not been examined in bipolar disorder.”

They measured CRP in 107 subjects with bipolar disorder correlated with Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) as a metric for cognitive function and found a significant association:

“There was a significantly increased odds of low RBANS total score for individuals who had a CRP level higher than the 90th percentile and the 75th percentile of the control group. There was an inverse relationship between CRP levels and performance on RBANS total ; RBANS immediate memory; RBANS attention; RBANS language…”

The authors conclude:

Inflammation may play a major role in the cognitive deficits associated with bipolar disorder.”

 

NeuropsychobiologyCRP also sorts out as a marker of brain inflammation in a study recently published in the journal Neuropsychobiology:

C-reactive protein (CRP), a marker of underlying low-grade inflammation, has been associated with the pathophysiology of bipolar disorder. Additionally, bipolar disorder may be accompanied by functional or structural cerebral alterations. We attempted to discover whether serum high-sensitivity CRP (hs-CRP) levels are linked to the structural volume change of a specific brain region along with cognitive performance.”

Examining the correlation between orbitofrontal cortex volume, CRP and cognitive function in bipolar disorder the authors conclude:

Elevation of serum hs-CRP levels, an indicator of inflammation, may be associated with reduced volume of the orbitofrontal cortex. Persistent inflammation in the euthymic phase of bipolar disorder may involve the pathogenesis or pathophysiology of alteration of the frontal pathway.”

 

Journal of Psychiatric ResearchCytokines, ‘immune messenger molecules of inflammation’, are naturally also observed in bipolar disorder as documented in a meta-analysis recently published in the Journal of Psychiatric Research:

“Bipolar disorder may be associated with peripheral immune system dysfunction…Our aim was to systematically review evidence of peripheral cytokine alterations in bipolar disorder integrating findings from various affective states.”

The authors conducted a meta-analysis of eighteen studies with a total of 761 bipolar disorder patients and 919 healthy controls comparing cytokine concentrations and found…

“Overall, concentrations of soluble Interleukin (IL)-2 receptor (sIL-2R), tumor necrosis factor-α (TNF-α), soluble tumor necrosis factor receptor type 1 (sTNFR1) and IL-4 were significantly higher in bipolar patients compared with healthy controls.”

 

Trends in ImmunologyOf course, pro-inflammatory cytokines have been recognized in the pathophysiology of depression for years as described in a much earlier paper published in the journal Trends in Immunology:

“Increasing amounts of data suggest that inflammatory responses have an important role in the pathophysiology of depression. Depressed patients have been found to have higher levels of proinflammatory cytokines, acute phase proteins, chemokines and cellular adhesion molecules. In addition, therapeutic administration of the cytokine interferon-α leads to depression in up to 50% of patients. Moreover, proinflammatory cytokines have been found to interact with many of the pathophysiological domains that characterize depression, including neurotransmitter metabolism, neuroendocrine function, synaptic plasticity and behavior.”

Regarding the role of stress and the autonomic nervous system in inflammation:

Stress, which can precipitate depression, can also promote inflammatory responses through effects on sympathetic and parasympathetic nervous system pathways.”

The two-hit model comes into play in the sense that earlier adaptations may set the stage for a subsequent trigger:

“…depression might be a behavioral byproduct of early adaptive advantages conferred by genes that promote inflammation.”

The authors conclude:

“These findings suggest that targeting proinflammatory cytokines and their signaling pathways might represent a novel strategy to treat depression.”

 

Medical HypothesesThe authors of a paper published in Medical Hypotheses describe pro-inflammatory cytokines as a mechanism shared by both bipolar disorder and migraine:

“A bi-directional association between mood disorders and migraine has been consistently reported… we review evidence for the role of inflammatory cytokines in the neurobiology of bipolar disorder and migraine. In addition, inflammation is hypothesized to be a shared pathophysiological mechanism subserving the bipolar disorder and migraine concomitance.”

And it stands to reason that…

“A derivative of this hypothesis is that pharmacological treatments primarily targeting the inflammatory system may have symptom suppressing effects in bipolar disorder.”

 

Journal of Affective DisordersAnother study published in the Journal of Affective Disorders examines the specific inflammatory cytokine tumor necrosis factor-alpha (TNF-α) in regard to bipolar disorder and response to lithium:

“The role of inflammation in bipolar disorder has recently emerged as a potential pathophysiological mechanism. Tumor necrosis factor-alpha (TNF-α) modulation may represent a pathogenic molecular target and a biomarker for staging bipolar disorder. In this context, the possible association between lithium response and TNF-α level was examined.”

The authors assessed the TNF-α level in 60 bipolar patients receiving lithium therapy in correlation with the ALDA lithium response scale (LRS) to evaluate longitudinal lithium response and found a clear association:

“There was a significant increase in TNF-α level in patients with poor lithium response compared to those with good response, also after controlling for a range of potential confounders.”

Their conclusion is significant both for the role of inflammation marked by TNF-α in bipolar disorder and case management utilizing lithium:

“This study strengthens the hypothesis that TNF-α level may mark or mediate lithium response, and that continuous immune imbalance in poor lithium responders may occasion treatment resistance. Further investigation of immune alterations in treatment-resistant bipolar patients may be productive.”

 

BMC MedicineThe key clinical questions are (1) what are the underlying causes of inflammation? and (2) what sound therapies can be applied to those causes? A paper published recently in BMC Medicine discusses several common contributing causes:

“We now know that depression is associated with a chronic, low-grade inflammatory response and activation of cell-mediated immunity, as well as activation of the compensatory anti-inflammatory reflex system. It is similarly accompanied by increased oxidative and nitrosative stress (O&NS), which contribute to neuroprogression in the disorder. The obvious question this poses is ‘what is the source of this chronic low-grade inflammation?’

The authors discuss several well-known factors including psychosocial stressors, poor diet, physical inactivity, obesity, smoking, altered gut permeability, atopy, dental cares, sleep and vitamin D deficiency. And neuroinflammation is shared characteristic of bipolar disorder, depression, schizophrenia, PTSD, and other psychiatric illnesses:

“There is also evidence that many other major psychiatric disorders are accompanied by activation of inflammatory and cell-mediated immune pathways, for example, mania, schizophrenia, post-traumatic stress disorder (PTSD)…A recent meta-analysis confirmed that mania and bipolar disorder are accompanied by activation of inflammatory, cell-mediated and negative immunoregulatory cytokines. Based on the first results obtained in schizophrenia, Smith and Maes in 1995 launched the monocyte-T lymphocyte theory of schizophrenia, which considered that activation of immuno-inflammatory processes may explain the neurodevelopmental pathology related to gestational infections. Results of recent meta-analyses showed that schizophrenia is accompanied by activation of inflammatory and cell mediated pathways. PTSD patients also show higher levels of pro-inflammatory cytokines, including IL-1, IL-6 and TNFα…It is evident that the sources of inflammation and immune activation, which play a role in depression, may contribute to the inflammatory burden in patients with mania. Schizophrenia is also associated with some but not all sources of inflammation and immune activation that play a role in depression. For example, a recent review showed that stress and trauma (first and second hits), nutritional factors and vitamin D may play a role in schizophrenia. The strong associations among schizophrenia and smoking, obesity, some atopic disorders, sleep disorders and poor periodontal and oral health may further contribute to the inflammatory burden in schizophrenia patients.”

Regarding the treatment and prevention of bipolar disorder, depression and other psychiatric illnesses the authors conclude:

“The pivotal element is that most of these are plastic, and amenable to intervention, both therapeutic and preventative…Psychiatry largely lacks an integrated model for conceptualizing modifiable risk factors for depression. It has, therefore, lacked conceptually and pragmatically coherent primary prevention strategies, prioritizing the treatment of established disorders. Yet the rationale, targets and imperative to focus on prevention of depression at a population level is clear.”

 

American Journal of PsychiatryFurther evidence for maternal infection as a trigger for autoimmune brain inflammation in bipolar disorder is presented in a study hot off the digital presses from the American Journal of Psychiatry:

“The authors examined whether serologically confirmed maternal exposure to influenza was associated with an increased risk of bipolar disorder in the offspring and with subtypes of bipolar disorder, with and without psychotic features.”

Their data disclosed a specific connection with bipolar disorder with psychotic features:

“…maternal serological influenza exposure was related to a significant fivefold greater risk of bipolar disorder with psychotic features…The results suggest that maternal influenza exposure may increase the risk for offspring to develop bipolar disorder with psychotic features. Taken together with earlier associations between prenatal influenza exposure and schizophrenia, these results may suggest that prenatal influenza is a risk factor for psychosis rather than for a specific psychotic disorder diagnosis.”

NEJM Journal WatchInterestingly, in a comment on this study published online in NEJM (New England Journal of Medicine) Journal Watch, psychiatrist Joel Yager, MD states:

“Together with research linking maternal influenza to schizophrenia risk, the current finding that influenza during pregnancy greatly increases the risk for bipolar disorder with psychotic features points to potentially similar prenatal mechanisms in the pathogenesis of diverse psychotic disorders. Other research suggests that prenatal priming of such vulnerabilities is in part due to prenatal immune activation of dopaminergic hyperactivity. Overall, such observations hint at common features and mechanisms in psychosis and may lead to better diagnostic conceptualizations.”

 

Progress in Neuro-Psychopharmacology and Biological PsychiatryIt stands to reason then that anti-inflammatory strategies must figure prominently in case management of bipolar disorder and other psychiatric conditions. The authors of a paper just published in Progress in Neuro-Psychopharmacology and Biological Psychiatry highlight the use of anti-inflammatory agents:

“Mood disorders have been recognized by the World Health Organization (WHO) as the leading cause of disability worldwide. Notwithstanding the established efficacy of conventional mood agents, many treated individuals continue to remain treatment refractory and/or exhibit clinically significant residual symptoms, cognitive dysfunction, and psychosocial impairment. Therefore, a priority research and clinical agenda is to identify pathophysiological mechanisms subserving mood disorders to improve therapeutic efficacy…During the past decade, inflammation has been revisited as an important etiologic factor of mood disorders.”

Furthermore, the depredations of brain inflammation encompass a wide range:

“Accumulating evidence implicates inflammation as a critical mediator in the pathophysiology of mood disorders. Indeed, elevated levels of pro-inflammatory cytokines have been repeatedly demonstrated in both major depressive disorder (MDD) and bipolar disorder (BD) patients. Further, the induction of a pro-inflammatory state in healthy or medically ill subjects induces ‘sickness behavior’ resembling depressive symptomatology…Potential mechanisms involved include, but are not limited to, direct effects of pro-inflammatory cytokines on monoamine levels, dysregulation of the hypothalamic–pituitary–adrenal (HPA) axis, pathologic microglial cell activation, impaired neuroplasticity and structural and functional brain changes.”

They identify several anti-inflammatory agents under investigation:

“Anti-inflammatory agents, such as acetyl-salicylic acid (ASA), celecoxib, anti-TNF-α agents, minocycline, curcumin and omega-3 fatty acids, are being investigated for use in mood disorders. Current evidence shows improved outcomes in mood disorder patients when anti-inflammatory agents are used as an adjunct to conventional therapy…”

 

Bipolar DisordersFoods, especially gluten and casein, must never be overlooked as potential triggers of neuroinflammation in bipolar disorder. A study recently published in the journal Bipolar Disorders focuses on this clinically important topic. The authors are also attentive to the issue of gastrointestinal inflammation and compromised barrier function as a sensitizing factor:

Immune sensitivity to wheat glutens and bovine milk caseins may affect a subset of individuals with bipolar disorder. Digested byproducts of these foods are exorphins that have the potential to impact brain physiology through action at opioid receptors. Inflammation in the gastrointestinal (GI) tract might accelerate exposure of food antigens to systemic circulation and help explain elevated gluten and casein antibody levels in individuals with bipolar disorder.”

They examined GI inflammation using ASCA in 207 non‐psychiatric controls, 226 in patients with bipolar disorder without a recent onset of psychosis, and 38 patients with bipolar disorder with a recent onset of psychosis, comparing it to antibodies against gluten, casein, Epstein–Barr virus (EBV), herpes simplex virus 1 (HSV‐1), influenza A, influenza B, measles, and Toxoplasma gondii and found a marked association with gluten and casein:

Elevated ASCA conferred a 3.5–4.4‐fold increased odds ratio of disease association that was independent of type of medication received. ASCA correlated with food antibodies in both bipolar disorder groups, and with measles and T. gondii immunoglobulin G (IgG) in the recent onset psychosis bipolar disorder group.”

The authors conclude:

Elevated seropositivity of a GI‐related marker and its association with antibodies to food‐derived proteins and self‐reported GI symptoms suggest a GI comorbidity in at least a subgroup of individuals with bipolar disorder. Marker seroreactivity may also represent part of an overall heightened activated immune state inherent to this mood disorder.”

 

Case management of neuroinflammation and the numerous and complex elements of autoimmunity could hardly be covered in a massive textbook much less a post here. A few among many potential therapeutic agents can be considered here by way of example.

Neurochemisty InternationalThe authors of a paper just published in the journal Neurochemistry International offering interesting evidence that alpha-lipoic acid can protect against neuroinflammation in neuropsychiatric disorders:

“Double-stranded RNAs (dsRNA) serve as viral ligands that trigger innate immunity in astrocytes and microglial…Beneficial transient TLR3 and PKR anti-viral signaling can become deleterious when events devolve into inflammation and cytotoxicity.”

Moreover…

Viral products in the brain cause glial cell dysfunction, and are a putative etiologic factor in neuropsychiatric disorders, notably schizophrenia, bipolar disorder, Parkinson’s, and autism spectrum.”

Of great clinical interest as a benign physiologic intervention…

Alpha-lipoic acid (LA) has been proposed as a possible therapeutic neuroprotectant. The objective of this study was to test our hypothesis that LA can control untoward antiviral mechanisms associated with neural dysfunction.”

They treated glial cultures viral mimetic dsRNA LA reduction of the effects of glial signaling, in other words a dampening of inflammation signaling:

LA blunted the dsRNA-stimulated expression of IFNα/β-inducible genes Mx1, PKR, and TLR3. And in polyI:C treated cells, LA promoted gene expression of rate-limiting steps that benefit healthy neural redox status in glutamateric systems. To this end, LA decreased dsRNA-induced inflammatory signaling by downregulating IL-1β, IL-6, TNFα, iNOS, and CAT2 transcripts.”

Considering the crucial role of glutathione metabolism and glutamate expression in regulation of neuroimmunity, their findings in this regard are of particular interest:

“In the presence of polyI:C, LA prevented cultured glial cytotoxicity which was correlated with increased expression of factors known to cooperatively control glutamate/cystine/glutathione redox cycling, namely glutamate uptake transporter GLAST/EAAT1, γ-glutamyl cysteine ligase catalytic and regulatory subunits, and IL-10. Glutamate exporting transporter subunits 4F2hc and xCT were downregulated by LA in dsRNA-stimulated glia. l-Glutamate net uptake was inhibited by dsRNA, and this was relieved by LA. Glutathione synthetase mRNA levels were unchanged by dsRNA or LA.

Clinicians should consider the authors’ conclusion:

“This study demonstrates the protective effects of LA in astroglial/microglial cultures, and suggests the potential for LA efficacy in virus-induced CNS pathologies, with the caveat that antiviral benefits are concomitantly blunted. It is concluded that LA averts key aspects of TLR3- and PKR-provoked glial dysfunction, and provides rationale for exploring LA in whole animal and human clinical studies to blunt or avert neuropsychiatric disorders.”

 

Medical HypothesesCucurmin, of course, is always worthy of consideration in case management of inflammatory and autoimmune disorders. The authors of a paper published last spring in Medical Hypotheses comment on the use of curcumin for bipolar disorder:

“Curcumin is a polyphenolic nonflavonoid compound extracted from the rhizome of turmeric (Curcuma longa)…Curcumin putative targets, known based on studies of diverse central nervous system disorders other than bipolar disorders (BD) include several proteins currently implicated in the pathophysiology of BD. These targets include, but are not limited to, transcription factors activated by environmental stressors and pro-inflammatory cytokines, protein kinases (PKA, PKC), enzymes, growth factors, inflammatory mediators, and anti-apoptotic proteins (Bcl-XL). Herein, we review previous studies on the anti-inflammatory and anti-oxidant properties of curcumin and discuss its therapeutic potential in BD.”

 

BMC MedicineInterestingly, aspirin is a potential therapeutic agent for bipolar disorder and other mental illnesses. An excellent paper recently published in BMC Medicine extensively reviews the mechanisms for its beneficial effects. Regarding the position of aspirin and other anti-inflammatory agents in the evolution of therapy for neuropsychiatric disorders:

“Historically, treatment options for common neuropsychiatric disorders, including depression, schizophrenia, and bipolar disorder, have focused on medications that modify the activity of monoamine neurotransmitter systems. Monoamines may play a large role in the pathophysiology of these disorders, but the monoaminergic theory of illness has failed to deliver novel agents beyond the limited treatment options currently available. There is now a clear body of recent evidence to support an etiologic role for other factors in the pathophysiology of depression, schizophrenia, and bipolar disorder, including oxidative and nitrosative stress (O&NS), mitochondrial dysfunction, and activation of the immune-inflammatory system.”

Specifically for aspirin:

“There is compelling evidence to support an aetiological role for inflammation, oxidative and nitrosative stress (O&NS), and mitochondrial dysfunction in the pathophysiology of major neuropsychiatric disorders, including depression, schizophrenia, bipolar disorder, and Alzheimer’s disease (AD). These may represent new pathways for therapy. Aspirin is a non-steroidal anti-inflammatory drug that is an irreversible inhibitor of both cyclooxygenase (COX)-1 and COX-2, It stimulates endogenous production of anti-inflammatory regulatory ‘braking signals’, including lipoxins, which dampen the inflammatory response and reduce levels of inflammatory biomarkers, including C-reactive protein, tumor necrosis factor-α and interleukin (IL)-6, but not negative immunoregulatory cytokines, such as IL-4 and IL-10. Aspirin can reduce oxidative stress and protect against oxidative damage. Early evidence suggests there are beneficial effects of aspirin in preclinical and clinical studies in mood disorders and schizophrenia, and epidemiological data suggests that high-dose aspirin is associated with a reduced risk of AD. Aspirin, one of the oldest agents in medicine, is a potential new therapy for a range of neuropsychiatric disorders, and may provide proof-of-principle support for the role of inflammation and O&NS in the pathophysiology of this diverse group of disorders.”

Regarding the autoimmune aspect:

“To further support a role for therapeutic agents targeting inflammation in psychiatry, there is a large body of evidence linking autoimmune disease to psychiatric disorders. For example, clinical depression is associated with diverse autoimmune disorders, including diabetes type 1 and 2, inflammatory bowel disease, psoriasis, rheumatoid arthritis, atherosclerosis, lupus erythematosus, and multiple sclerosis (MS). Patients with clinical depression have a high degree of auto-immunity directed against a number of different selfepitopes, including serotonin and phospholipids (for example, cardiolipin and antinuclear factor). Recently, a new type of autoimmune response has been described, which is an autoimmune response secondary to O&NS damage [oxidative and nitrosative damage]. Thus, it is possible that increased O&NS levels may damage endogenous molecules, such as fatty acids and proteins, thereby changing their structure. As a consequence, the O&NS-modified self determinants may be rendered immunogenic, and an autoimmune response is then directed against the modified epitopes (neo-epitopes). For example, clinical depression is accompanied by IgG-mediated immune responses directed against oxidized low-density lipoprotein. Moreover, there is an association between this kind of autoimmune response and progression (or staging) of depression. Consequently, some of these autoimmune responses are significantly higher in depressed individuals with chronic depression (duration of >2 years) compared with patients who are depressed but do not have chronic depression. These findings suggest that O&NS damage, the consequent formation of neo-epitopes, an enhancement of the natural autoimmune response, and even a transition to pathological damaging auto-immunity increase the risk of neuroprogression and of chronic depression.”

The authors also note the interplay between genetic potential and the expression of autoimmunity in bipolar disorder:

“Evidence from the literature on bipolar disorder also supports the role of a genetic component; patients with bipolar disorder and their relatives have been shown to be more prone to develop thyroid auto-immunity, and this association is not attributable to the use of lithium or to the severity of psychiatric symptoms. Moreover, in addition to a higher prevalence of thyroid autoantibodies, patients with bipolar disorder have a higher prevalence of organ-specific autoantibodies, including autoantibodies to hydrogen/potassium ATP and glutamic acid decarboxylase-65. The aforementioned Danish national study confirmed these findings by showing an association of bipolar disorder with a family history of pernicious anemia, and with presence of Guillain-Barré syndrome, inflammatory bowel disease, and autoimmune hepatitis in individual patients.”

As for indicating the use of aspirin:

“Collectively, these findings imply shared immune pathogenic factors for mood disorders, schizophrenia, and organ-specific autoimmune diseases. One of these shared factors is thought to be an intrinsically high activation set-point for the MPS [mononuclear phagocyte system, in this case monocytes present as microglia in the brain]. It is thought that the high activation set-point of these cells of the MPS can be down-regulated by aspirin.”

 

Bipolar DisordersWhile on the topic of aspirin, it’s worth noting a study published last summer in Bipolar Disorders offering evidence that aspirin improves lithium-related sexual in men with bipolar disorder:

“The aim of the present study was to assess the effect of aspirin on lithium‐related sexual dysfunction in men with stable bipolar affective disorder (BAD).”

The authors staged a randomized, double‐blind, placebo‐controlled study, in which 32 men with stable BAD who had been on lithium maintenance therapy randomly received aspirin (240 mg/day) or placebo for six weeks. They used the International Index for Erectile Function (IIEF) was used to assess sexual symptoms at the start, week 3, and week 6. The results were gratifying:

“Significant effects of time × treatment interaction were observed for total score [Greenhouse–Geisser: F(1.410,39.466) = 6.084, p = 0.010] and erectile function [Greenhouse–Geisser: F(1.629,45.602) = 7.250, p = 0.003]. By Week 6, patients in the aspirin group showed significantly greater improvement in the total (63.9% improvement from the baseline) and erectile function domain (85.4% improvement from the baseline) scores than the placebo group (14.4% and 19.7% improvement from the baseline). By Week 6, 12 (80%) patients in the aspirin group and three (20%) patients in the placebo group met the criteria of minimal clinically important change. Other IIEF domains also showed significant improvement at the end of the trial. The frequency of side effects was similar between the two groups.”

The authors conclude:

Aspirin effectively improves lithium‐related sexual dysfunction in men with stable BAD.”

Bottom line: There is a massive amount of evidence supporting the importance of assessing and treating neuroinflammation in bipolar disorder and other neuropsychiatric illnesses. This makes necessarily the comprehensive examination of autoimmunity and its numerous underlying contributory causes. Past and future posts focus on this crucial dimension of clinical practice.

Neuropsychiatric illness, autoimmunity and the role of microbes

Current Opinion in RheumatologyNeuropsychiatric illness often involves brain inflammation for which there may be an autoimmune origin. The authors of a paper* recently published in Current Opinion in Rheumatology set out to…

“…illustrate how microbes might participate in the pathogenesis of neuropsychiatric illness by triggering the production of autoantibodies that bind to brain targets.”

They describe the science emerging on underlying mechanisms behind the observations that both exposure to infectious agents and autoantibodies without evidence of pathogens can cause brain disorders…

“…….evidence accumulates to support the idea that dysregulated cross-talk between the brain and the immune system is an important contributor to the pathogenesis of conditions as diverse as schizophrenia, mood disorders, autism spectrum disorders (ASDs), obsessive-compulsive disorder (OCD), Tourette syndrome and other tic disorders, attention-deficit hyperactivity disorder (ADHD), anorexia nervosa, narcolepsy, posttraumatic stress disorder and myalgic encephalomyelitis/chronic fatigue syndrome (CFS). In addition, intriguing new evidence lends support to the possibility that not only the microbes associated with infectious episodes but also the bacteria of the gut microbiome can foster the production of brain-reactive autoantibodies, and that these microbe-induced antibodies provide the critical link between infection and neuropsychiatric disorders.”

In the case of infection, it may not even matter so much what the infectious agent is…

“A complication in delineating the relationship of a particular pathogen to a particular neuropsychiatric disorder is that even if the link is real, it may nonetheless be nonspecific, both in terms of the type of infectious agent capable of inducing brain dysfunction, as well as in the neurobehavioral features that follow. An expanding body of studies using animal models of infection-related developmental disorders reports persistent effects on offspring brain development and behavior following prenatal or early postnatal exposures to noninfectious agents that mimic actual infection with influenza virus, such as polyinosinic:polycytidylic acid (poly I:C, a form of synthetic, double-stranded RNA), or a bacterium, such as lipopolysaccharide (LPS, or bacterial endotoxin), illustrating the importance of maternal immune responses as modifiers of postinfectious sequelae in the offspring. Findings from these studies suggest that CNS damage requires the presence of innate immune and inflammatory molecules that disrupt brain development.”

Noting that shifts in maternal immune activation toward an autoimmune and allergic phenotype predisposed offspring to autism-like behaviors which were subsequently abolished by bone marrow transplantation to modify immune expression…

“In addition to this overlap in neurodevelopmental consequences after prenatal and postnatal virus-like and bacteria-like exposures, exposure of infant mice to environmental contaminants such as the organic compound, toluene, is associated with upregulated expression of cytokine genes in hippocampus. Thus, increasing evidence suggests that it is the presence of innate immune molecules, as opposed to direct infection of neurons and glial cells, that mediates these effects.”

While breaching of the blood brain barrier (BBB) immunoreactive agents into the privileged space of the central nervous system, it may not always be necessary for the manifestation of neuropsychiatric symptoms:

“Another study that focused on GAS [group A streptococcus]-related, CNS-directed autoimmunity raised the intriguing suggestion that alternate transport systems may exist for entry of certain immunoglobulin isotypes or subclasses into the CNS. Zhang et al. injected naïve mice with anti-GAS IgM monoclonal antibodies, without the use of an adjuvant to breach the BBB, and found increased stereotypic behaviors…Transcellular mechanisms that obviated the need to compromise BBB integrity were postulated to facilitate the entry of these IgM antibodies into the CNS.”

Pathogens aren’t the only microbes that can incite autoimmune activity. As noted in earlier posts, the ‘normal’ commensal microbiota can also participate in loss of immune tolerance:

“Recent evidence suggests that both pathogenic and commensal microbes play a role in the pathogenesis of a subset of neuropsychiatric disorders through induction of brain-reactive autoantibodies. Whereas infection with certain pathogens can trigger autoantibody production through molecular mimicry, commensal bacteria that comprise the gastrointestinal microbiota probably set the stage for the development of autoimmune responses by skewing immune responses toward overproduction of Th17 cells and reduction in numbers and function of Tregs.”

The authors also note the role of antioxidants and depletion of the antoxidant system, particularly glutathione:

Increased oxidative stress with diminished glutathione impairs Tregs, increasing autoimmunity.

Increased oxidative stress with diminished glutathione impairs Tregs, increasing autoimmunity.

Failed uptake of antioxidant precursors in the terminal ileum, influenced by differences in tryptophan degradation capacity of the microbiota and related factors, may also contribute to a skew toward autoimmunity by reducing levels of Tregs and increasing levels of autoimmunity-provoking Th17 cells.”

The link between schizophrenia and Toxoplasma gondii infection is illustrative:

“There is also evidence that the microbial infection itself is not likely to be as important in pathogenesis as the presence of antibodies to the microbe, as well as the isotype and binding characteristics (cross-reactivity, affinity and avidity) of these antibodies. Anti-toxoplasma antibodies may also be more prevalent in individuals with bipolar disorder, type 1.”

Moreover…

“In individuals with schizophrenia, antibodies directed against food antigens, including bovine milk casein and wheat-derived gluten, are correlated with the presence of antibodies to T. gondii…In a separate study, increased levels of anti-gliadin antibodies were found in individuals with schizophrenia. Furthermore, the interactomes of nine neuropsychiatric disorders, including multiple sclerosis, Alzheimer’s disease, schizophrenia, bipolar disorder, depression, childhood obesity, Parkinson’s disease, ADHD and ASD, but not anorexia nervosa or myalgic encephalomyelitis/CFS, showed significant overlap with the interactome of T. gondii, and has been closely associated with a number of autoimmune diseases.”

Interestingly, autoimmunity with loss of tolerance to gluten may involve reduced antioxidant capacity:

“The relationship of anti-toxoplasma antibodies to anti-gliadin antibodies in some neuropsychiatric disorders may relate to reduced antioxidant capacity in the terminal ileum. Gliadin, a major protein component of wheat that is associated with celiac disease, also appears able to dysregulate redox balance in peripheral blood mononuclear cells, triggering allergic-type responses that include specific enhancement of IL-4-mediated IgE production…A clearer understanding of these processes may uncover unique strategies for intervention with less potential for toxicity, including antioxidants, prebiotics, probiotics and transplantation of fecal microbiota.”

Clinical note: Clearly practitioners must be alert to the role of autoimmunity in neuropsychiatric disorders and must discriminate between infection and loss of immune tolerance triggered by infection. It may not be so apparent that the indigenous commensal microbiota can play a role in autoimmunity, antimicrobial therapy may modify symptoms for a time but ‘dig the hole deeper’, and that caution must be observed in contemplating treatment for infections that expose the immune system to the lipopolysaccharides of disintegrating bacterial and fungal cells in the presence of active or latent loss of immune tolerance.

The authors conclude:

“Genetically susceptible individuals may generate brain-reactive autoantibodies when exposed to certain infectious agents or commensal organisms. Under inflammatory conditions that promote BBB disruption and facilitate trafficking into the CNS, binding of autoantibodies to cross-reactive epitopes may contribute to the cognitive and behavioral disturbances associated with these disorders by altering brain activity within key circuitry. This conceptual model views altered brain–immune signaling as a product of the interaction of immune response genes and microbial exposures at key points during prenatal and postnatal development, and provides a framework within which discordant findings across studies of different neuropsychiatric disorders may be better explained and through which novel pathways for improved therapeutics may be discovered.”

* The entire paper can be read in Medscape Family Medicine.

Adolescent decline in verbal ability can predict psychosis in adulthood

JAMA Psychiatry Vol 70 No 1It’s well recognized that cognitive deficits in childhood or adolescence typically precede the onset of psychosis, but the studies done up until now have not determined whether the association is prodromal (an early symptom of psychosis itself) or neurodevelopmental (problems with brain development and maturation that set the stage for later psychosis). A study just published in JAMA Psychiatry offers strong evidence that verbal decline in adolescence reflects neurodevelopmental defects that significantly increase the lifetime risk for psychosis. The authors note:

“Clear evidence from many prospective, population-based studies indicates that patients who develop psychosis in adulthood experienced various cognitive deficits during childhood and adolescence. However, it is unclear whether these deficits become more severe during adolescence.”

So they set out to…

“…assess the influence of cognitive developmental trajectories in adolescence and young adulthood on the risk for psychosis in adulthood.”

They conducted a longitudinal cohort study of four populations of adolescent boys and young men born in in 1953, 1967, 1972, and 1977, totaling 10,717 individuals. These subjects were followed through December 2006 and tested for verbal, spatial, and inductive ability at age 13 years. Equivalent tests were performed during army conscription at 18 years (this was done in Sweden). The authors correlated this data with hospital admissions for nonaffective or affective psychoses in adulthood. A striking link with decline in verbal ability emerged:

“A relative decline (compared with the unaffected population) in verbal ability between ages 13 and 18 years was associated with increased risk for schizophrenia and for other nonaffective and affective psychoses. Decline between ages 13 and 18 years was a much stronger predictor of psychosis than the verbal ability score at age 18 years alone. The association remained significant after adjustment for urbanicity, parental educational level, and family history of psychosis and persisted when cases with onset before age 25 years were excluded, indicating that this was not a prodromal effect.”

Note for clinicians and parents: multiple biological factors can conspire to interfere with neurodevelopment, manifesting as disturbances in cognitive and emotional function. A range of these with reference to pertinent tests, validating citations and practical remediation is available in the Parents’ Guide To Brain Health. The authors conclude:

A relative decline in cognitive performance in adolescence and young adulthood, particularly in verbal ability, is associated with increased risk for psychosis in adulthood, and a relative decline in verbal ability between ages 13 and 18 years is a stronger predictor of psychosis than verbal ability at age 18 years alone. This suggests an impairment of late neurodevelopment affecting the acquisition of verbal skills in adolescent boys and young men who later develop psychosis.”

Lyme disease, neuropsychiatric symptoms and autoimmunity

As with other chronic infections, the most devastating effects of Lyme disease can occur from the immune system losing tolerance for normal tissue as it cross-reacts while attacking the pathogen. A paper just published in The Open Neurology Journal reviews the body of knowledge on the neuropsychiatric symptoms of Lyme disease and other infections as an immune mediated neurodegenerative disorder, enlarged by a wealth of citations. The author states:

“Disease progression of neuropsychiatric symptoms in Lyme/tick-borne diseases can be better understood by greater attention to psychoimmunology. Although there are multiple contributors that provoke and weaken the immune system, infections and persistent infections are significant causes of pathological immune reactions. Immune mediated effects are a significant contributor to the pathophysiological processes and disease progression.”

He expands on neurodegeneration and immune-mediated inflammation such as occurs in Lyme disease, depression and Alzheimer’s disease:

“When neurodegenerative diseases are progressive uncontrolled inflammation drives disease progression. Substantial evidence has documented a common inflammatory mechanism in various neurodegenerative diseases. It has been hypothesized that in the diseased CNS, interactions between damaged neurons and dysregulated, overactivated microglia create a vicious self-propagating cycle causing uncontrolled, prolonged inflammation that drives the chronic progression of neurodegenerative diseases. There is evidence with depression, Alzheimer’s disease (AD), schizophrenia and epilepsy to support this position. A meta-analysis of cytokines in major depression including 24 studies reports significantly higher concentrations of the proinflammatory cytokines TNF-alpha and IL-6 in depressed subjects compared with control subjects. A meta-analysis of cytokines in AD which reviewed 86 studies strengthens the clinical evidence that AD is accompanied by an inflammatory response with particularly higher peripheral concentrations of IL-6, TNF, IL-1, transforming growth factor, IL-12 and IL-18 and higher CSF concentrations of transforming growth factor.”

Schizophrenia is included in the list of autoimmune neurodegenerative disorders:

Hundreds of studies of schizophrenic illness in adults have documented immunological abnormalities in these patients. First-episode psychosis in children is associated with evidence of increased inflammation. Increasing evidence now suggests that the glia, cerebral vasculature, and the BBB may be involved which support the inflammatory theory of schizophrenia that was formulated over a 100 years ago.”

Epilepsy, of course, is also included:

There is a rapidly growing body of evidence that supports the involvement of inflammatory mediators in epilepsy—released by brain cells and peripheral immune cells—in both the origin of individual seizures and the epileptogenic process. Aspects of brain inflammation and immunity were first described and subsequently, it was demonstrated how seizures cause inflammation, and whether such inflammation, in turn, influences the occurrence and severity of seizures, and seizure-related neuronal death.”

The astute clinician must also bear in mind associated phenomena that support the autoimmune inflammatory process in Lyme disease and other neurodegenerative conditions:

“Oxidative stress and oxygen free radicals or activated oxygen has been implicated in diverse environmental stresses and appears to be a common contributor in neurodegenerative diseases…Excitotoxicity and inadequate remethylation leads to increased homocysteine levels which are excitotoxic [33]. Elevated C-reactive protein levels are linked to a decline in executive function and frontal lobe damage…Proinflammatory cytokines include Interferon alpha, IL-1-beta and IL-6. Cytokine activation has been associated with psychiatric symptoms. For example, IL-6 is elevated in the cerebrospinal fluid of suicide attempters and is related to symptom severity, memory deficits and aggressiveness and IL-1-beta is associated with self-inflicted aggressive behavior and fatigue.”

Practitioners who are fuzzy on serotonin dynamics will appreciate their review of how infections by parasites and pathogens like Borrelia burgdorferi in Lyme disease pervert the metabolism of serotonin in such a way that serotonin support can worsen depression. Clinicians who attempt to modulate serotonin with either reuptake inhibitors or precursor therapy must be aware of the following:

“Inflammation provoked by parasites impacts the conversion of tryptophan into serotonin. The kynurenine pathway is a major route of L-tryptophan catabolism into serotonin with a number of metabolites that include—kynurenic acid which is an N-Methyl-D-aspartic acid (NMDA) antagonist (neuroprotective, unless excessive), quinolinic acid which is a NMDA agonist (neurotoxic). In an inflammatory state there is decreased serotonin & a shift to quinolinic acid rather than kynurenic acid. The enzyme indoleamine 2,3-dioxygenase (IDO), which converts tryptophan into kynurenine and which is stimulated by proinflammatory cytokines, is implicated in the development of interferon–induced depressive symptoms, first by decreasing the serotonin availability to the brain and second by the induction of the kynurenine pathway resulting in the production of neurotoxic metabolites. In persistent infections associated with persistent inflammation, chronic activation of TNF-alpha stimulates interferon-gamma, which overactivates IDO, the rate-limiting enzyme for catabolism of tryptophan in the brain. Overactivated IDO causes neurotoxicity, and immune suppression of cytotoxic T cells.”

So attempting to increase serotonin under these conditions is prone to backfire. Moreover…

“Underactivation of IDO is known to cause autoimmune reactions, but it has recently been discovered that overactivated IDO causes autoimmune B cell antibody production. CSF quinolinic acid is significantly elevated in a number of CNS infections including Borrelia burgdorferi (Bb), infection—dramatically in patients with CNS inflammation, less in encephalopathy. The presence of this known agonist of NMDA synaptic function; a receptor involved in learning, memory, and synaptic plasticity; may contribute to the neurologic and cognitive deficits seen in many Lyme disease patients.”

The author also comments on the polar character of the immune imbalance associated with Lyme disease:

“Some immune mediated pathophysiology seen in Lyme/Tick-Borne Diseases (LYD/TBD) is a failure to shift from Th1 to Th2. Persisting immune activation causes the cytokine storm in chronic Lyme. In these patients, the innate immune system is not turned off by a series of specific immune peptides…The magnitude of IL-6 in human serum and CSF has been shown to correlate with disease activity in neurologic Lyme disease. Elevated levels of IL-6 can cause symptoms of fatigue and malaise, common to many infectious conditions as well as Lyme disease. Borrelia species induce activation of IL-17 production. The chemokine CXCL13 is a key regulator of B cell recruitment to the cerebrospinal fluid in acute Lyme neuroborreliosis CSF CXCL13 and can be used as a diagnostic marker for infection.”

Persistently elevated IL-17 is an insignia of autoimmunity.

Lyme disease neuropsychiatric phenomena are similar to psychiatric morbidities following strep infection:

“Paraneoplastic limbic encephalopathies and pediatric autoimmune diseases associated with strep (PANDAS) are good models to understand the effects of autoantibodies directed against intracellular neuronal antigens and the associated psychiatric symptoms. In paraneoplastic and nonparaneoplastic limbic encephalitis, voltage-gated potassium channel limbic encephalitis, Hashimoto’s encephalopathy, anti-NMDA and other glutamate receptor encephalitis, encephalitis associated with gamma-aminobutyric acid signaling and systemic lupus erythematosus neurons are excited to death by autoantibodies resulting in neurotoxicity. PANDAS is an interaction of a Streptococcal infection in a genetically susceptible individual at a young age which can result in obsessive compulsive disorder, tics and sometimes attention span difficulties. PANDAS is often comorbid with LYD/TBD and the broader categorization has been referred to as pediatric infection-triggered autoimmune neuropsychiatric disorders. Symptom flares follow a strep infection and correlate with increased antibody production.”

Specifically, antigens on the surface of Borrelia can trigger an immune inflammatory response that cross-reacts with the host’s neuronal tissues:

Lyme surface antigens can cause molecular mimicry and associated autoimmune symptoms. Bb spirochetes surface glycolipids may elicit cross-reactive antibodies and IgM Bb flagella antibodies cross-reacted with neuronal antigens. Anti-neural antibody reactivity has been demonstrated in patients with a history of Lyme borreliosis and persistent symptoms. Anti-neural antibody reactivity was found to be significantly higher in the Lyme patients with prior treatment and persistent symptoms (PLS) group than in the post-Lyme healthy and normal healthy groups. Immunohistochemical analysis of PLS serum antibody activity demonstrated binding to cells in the central and peripheral nervous systems. The presence of anti-neural antibody reactivity in patients with PLS demonstrates ‘objective immunologic abnormalities’ and underscores the pathophysiologic nature of PLS and discredits the psychosomatic theory advanced by some as the cause of persisting symptoms.”

He also considers the autoimmune dimension of autism spectrum disorders (ASD):

“There has been recent attention to the association between chronic infections, LYD/TBD and autism spectrum disorders (ASD). Immune reactivity associated with these infections in the mother, fetus and child appear to adversely affect developing neural tissue and contribute to the pathophysiology associated with autism spectrum disorders. Possible pathophysiological mechanisms include both inflammatory processes as well as autoantibodies to developing neural tissueIndividuals with autism show increased pro-inflammatory cytokines in the brain, as well as activation of microglia. Additionally, antibodies that target brain tissues have been described in both children with autism and their mothers…Autoantibodies targeting brain proteins have been discovered in both children with autism and their mothers and circulating maternal autoantibodies directed toward fetal brain proteins are highly specific for autism…In addition, antibodies that react to the 36, 37, 39, 61 and/or 73 kDa bands on Western Blot testing are associated with provoking an immune reaction and contribute to causing autism. Reactivity to these bands is also associated with Borrelia burgdorferi and to a lesser degree to Bartonella henselae, Bartonella quintana, Mycoplasma, Chlamydia pneumonia and Streptococcus pneumoniae.”

Besides a reminder of factors that practitioners must bear in mind when managing Lyme disease or post-Lyme disease conditions, the author has covered important points for psychiatric disease in general. Readers may wish to see some of the 64 citations referenced in this paper by clicking on the link above. The author concludes:

“When looking at the clinical and basic science research on the subject articles it is apparent that persistent infection and associated inflammation and molecular mimicry mechanisms are associated with gradually increasing encephalopathy and gradually increasing mental symptoms. Cognitive symptoms begin as executive dysfunction and mild cognitive impairments and may gradually progress to dementia while emotional symptoms begin with insomnia, reduced frustration tolerance, irritability and dysthymia and may progress to anxiety disorders, depression, impulsivity and personality disorders and subsequently psychosis and/or suicidal and homicidal tendencies. Many of the neurological, cognitive and psychiatric symptoms associated with LYD/TBD appear to be mediated by immune mechanisms.”

Schizophrenia, brain inflammation and depression

Schizophrenia shares underlying causal mechanisms with depression that are important for case management and treatment. A paper just published in the journal Progress in Neuro-Psychopharmacology and Biological Psychiatry highlights key features of the inflammatory process in schizophrenia that clinicians should be aware of. The authors state:

Schizophrenia and depression are two common and debilitating psychiatric conditions. Up to 61% of schizophrenic patients have comorbid clinical depression, often undiagnosed. Both share significant overlaps in underlying biological processes, which are relevant to the course and treatment of both conditions.”

All of these processes in both schizophrenia and depression are linked in some way to inflammation:

“Shared processes include changes in cell‐mediated immune and inflammatory pathways, e.g. increased levels of pro-inflammatory cytokines and a Th1 response; activation of oxidative and nitrosative stress (O&NS) pathways, e.g. increased lipid peroxidation, damage to proteins and DNA; decreased antioxidant levels, e.g. lowered coenzyme Q10, vitamin E, glutathione and melatonin levels; autoimmune responses; and activation of the tryptophan catabolite (TRYCAT) pathway through induction of indoleamine-2,3-dioxygenase. Both show cognitive and neurostructural evidence of a neuroprogressive process.”

The authors assert that patients with schizophrenia are immunologically predisposed to depression:

“Here we review the interlinked nature of these biological processes, suggesting that schizophrenia is immunologically primed for an increased expression of depression. Such a conceptualization explains, and incorporates, many of the current perspectives on the nature of schizophrenia and depression, and has implications for the nature of classification and treatment of both disorders.”

As readers here likely know, latent autoimmune phenomena are often triggered by infection. The authors discuss how this comes into play in promoting and differentiating schizophrenia and depression in regard to maternal infections.

“An early developmental etiology to schizophrenia, driven by maternal infection, with subsequent impact on offspring immuno-inflammatory responses, creates alterations in the immune pathways, which although priming for depression, also differentiates the two disorders.”

For concerned clinicians this offers a rich assortment of pathways that can be investigated with appropriate tests as candidates for interventional support.

Relevant to this topic is a presentation on psychiatric conditions as immune disorders entitled Redefining Psychiatric and Neurologic Co-morbidities as Systemic Dysfunction delivered at the Autoimmunity Congress Asia in Singapore last September by Dr Roswitha Goetze-Pelka of the Ev. Krankenhaus Bethanien in Greifswald, Germany: