Bipolar disorder and neuroinflammation

Bipolar 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."

 In 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."

 A 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."

 In 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."

Moreover...

"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."

 The 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."

 Inflammatory 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."

 A 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."

 CRP 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."

 Cytokines, '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."

 Of 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."

 The 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."

 Another 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."

 The 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."

 Further 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."

Interestingly, 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."

 It 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..."

 Foods, 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.The 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."

 Cucurmin, 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."

 Interestingly, 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."

 While 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.For information on bipolar disorder and sleep see this resource.