Immune Dysregulation and Autoimmunity in Bipolar Disorder

ANP471210.1177/0004867413499077ANZJP ArticlesRege and Hodgkinson 4990772013

Review

Australian & New Zealand Journal of Psychiatry 47(12) 1136–1151 Immune dysregulation and DOI: 10.1177/0004867413499077 © The Royal Australian and autoimmunity in bipolar disorder: New Zealand College of Psychiatrists 2013 Reprints and permissions: Synthesis of the evidence and its sagepub.co.uk/journalsPermissions.nav clinical application anp.sagepub.com

Sanil Rege1,2,3 and Suzanne J Hodgkinson4,5

Abstract Objective: 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. Method: This article reviews the literature on peripheral and central immune dysregulation and autoimmunity in bipolar disorder. The mechanisms of the innate and adaptive immune systems in the pathophysiology of bipolar disorder are explored. The clinical features and pathogenesis of neuropsychiatric systemic lupus erythematosus, anti-NMDA encephalitis, and Hashimoto’s encephalopathy are summarized. Results: 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. Neu- ropsychiatric systemic lupus erythematosus, anti-NMDA encephalitis, and Hashimoto’s encephalopathy are important differentials for a psychiatrist to consider when suspecting autoimmune encephalopathy. Conclusions: 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.

Keywords Anti-NMDA encephalitis, autoimmunity, bipolar disorder, cytokines, Hashimoto’s encephalopathy, immune dysregulation, microglia, neuroinflammation, neuropsychiatric systemic lupus erythematosus, oligodendrocytes

Introduction 2010). More recently, evidence has accumulated suggesting that inflammation and immune dysregulation play an The greatest mistake in the treatment of diseases is that there important role in neuroprogression in bipolar disorders are physicians for the body and physicians for the soul, (Berk et al., 2011). although the two cannot be separated (Plato)

1Peninsula Health Mental Health Service, Frankston, Australia Our understanding of the role of the immune system and 2Positive Psychology Wellness Centre, Mornington, Australia autoimmunity in psychiatry is evolving. A large body of 3Psych Scene, Australia evidence points to a role for inflammatory mediators 4University of New South Wales (UNSW), Sydney, Australia and immune dysregulation in the pathogenesis of psychiat- 5Liverpool Hospital, Liverpool, Australia ric disorders such as schizophrenia, depression, and Corresponding author: Alzheimer’s disease (Fan et al., 2007; Krishnadas and Sanil Rege, 1 Ross Street, Mornington, VIC 3931, Australia. Cavanagh, 2012; Moscavitch et al., 2009; Zotova et al., Email: [email protected]

Australian & New Zealand Journal of Psychiatry, 47(12) Rege and Hodgkinson 1137

The link between autoimmunity and psychiatric symp- component of cell-mediated immunity. An optimal balance toms has long been recognized, and W. Osler offered a between anti-inflammatory and pro-inflammatory cytokines description of psychosis in systemic lupus erythematosus is vital for the optimal functioning of the immune response (SLE) in 1895. In neurology, the identification of a range of (Ng et al., 2003). B cells, however, play an important role in autoantibodies acting on specific synaptic sites in the brain antibody-mediated or humoral immunity through the pro- has been an important development as these disorders can duction of antibodies against foreign antigens. present initially to psychiatrists. This requires psychiatrists The majority of the studies on bipolar disorder have to remain vigilant for the possibility of autoimmune disor- focussed on cell-mediated immunity by measuring inflam- ders mimicking psychiatric syndromes (Davison, 2012; matory markers and cytokines, finding specific patterns of Rosenfeld and Dalmau, 2011). Because the brain can be cytokine levels. A recent large meta-analysis showed ele- affected by various autoimmune processes, it is possible vated levels of TNF-α, soluble tumour necrosis factor that some psychiatric disorders may have an autoimmune receptor type 1 (sTNF-R1) and soluble interleukin-2 recep- basis. We review the literature on peripheral and central tor (sIL-2R) in manic patients, compared to healthy control nervous system (CNS) immune dysregulation and autoim- subjects and euthymic bipolar patients. The levels of sTNF- munity in bipolar disorder. The mechanisms of the innate R1 were also elevated in bipolar euthymic patients com- and adaptive immune systems in the pathophysiology of pared to healthy control subjects (Munkholm et al., 2013). bipolar disorder are explored. The clinical features and In addition to the presence of elevated acute-phase proteins, pathogenesis of neuropsychiatric systemic lupus erythema- including haptoglobin and C-reactive protein, complement tosus, anti-NMDA encephalitis, and Hashimoto’s encepha- levels, such as C3C and C4 concentrations, have been lopathy are summarized. found to be elevated in bipolar disorder (Maes et al., 1997; O’Brien et al., 2006; Wadee et al., 2002). There appears to Evidence of immune dysregulation be a phasic difference in the level of cytokines in manic in bipolar disorder bipolar patients, who show elevated plasma levels of TNF- α, IL-2, and IL-4 (Ortiz-Dominguez et al., 2007). Increases The immune system can broadly be divided into the innate in the levels of IL-8 and IL-6 have been reported in and adaptive immune systems, or cell-mediated immunity depressed bipolar patients (Brietzke et al., 2009). There is and humoral immunity. The innate immune system is the evidence of stage-related abnormalities in cytokines; all first and immediate line of defence against pathogens; it interleukins and TNF-α are elevated in the early stages of consists of monocytes, monocyte-derived dendritic cells illness, whereas in the later stages of illness, TNF-α and and macrophages, neutrophils, natural killer cells, mast IL-6 continue to be elevated, but IL-10 does not. Thus, cells, and various cytokines and chemokines, such as inter- these cytokines may serve as important markers of disease feron (IFN) γ, interleukin (IL) 1, IL-6, and tumour necrosis progression in bipolar disorder (Kauer-Sant’Anna et al., factor α (TNF-α) (Fearon and Locksley, 1996). By contrast, 2009). Berk et al. (2011) have hypothesized that inflamma- adaptive immunity occurs after a latent phase and is primar- tory mediators are involved in the episode-related cognitive ily activated by antigen-presenting cells, which include decline seen in bipolar disorder. Bipolar patients in the macrophages and dendritic cells (Nguyen et al., 2002). The euthymic state also have abnormalities in their chemokine adaptive immune response, once activated through antigen levels that induce chemotaxis (i.e. the movement of leuko- recognition receptors on the surface of T cells called pattern cytes towards sites of inflammation), indicating ongoing recognition receptors, is mediated by T (CD4 and CD8) and inflammation in a clinically quiescent stage of illness B lymphocytes. CD8 T cells are cytotoxic and are responsi- (Brietzke et al., 2009). Leptin is an adipocyte-derived ble for destroying intracellular pathogens, whereas CD4 T cytokine that is of interest in the pathogenesis of bipolar cells or T-helper cells play critical roles in immunomodula- disorder as it plays an important role in obesity and pro- tion through the secretion of cytokines which are signalling motes Th1 cell differentiation modulating immune molecules involved in the on-going activation and recruit- responses (La Cava and Matarese, 2004). Insulin-like ment of immune cells (Zhu and Paul, 2008). The four key growth factor (IGF)-1 has been implicated in the pathogen- CD4 T cells are Th1, Th2, Th17, and Treg cells. Th1 cells esis of bipolar disorder, insulin resistance, and immune release pro-inflammatory cytokines, such as IFN γ, TNF, dysfunction and may be a future biomarker of interest and IL-2; Th2 cells release IL-4, IL-5, and IL-10, which act (Smith, 2010; Squassina et al., 2013). as regulators and anti-inflammatory cytokines and are responsible for activation of humoral immunity via the acti- Does neuroinflammation play a vation of B cells through IL-4 (Bellone, 2005; Mosmann role in the pathophysiology of and Sad, 1996; Waite and Skokos, 2012). Th17 and Treg bipolar disorder? cells play important but different roles in the pathogenesis of autoimmunity (La Cava, 2009; Stockinger and Veldhoen, Neuroinflammation is the result of an immune response in 2007). T cells and cytokines thus form an important the CNS that involves a complex interaction between the

Australian & New Zealand Journal of Psychiatry, 47(12) 1138 ANZJP Articles

CNS innate immune system, the blood–brain barrier (BBB) levels reduce postsynaptic serotonin receptors, serotonin and the peripheral immune system. Microglia are the first responsiveness, and brain-derived neurotrophic factor lev- line of defence in the CNS. Neuronal injury, infection, or els, thus affecting neurotransmitter regulation and neuro- ischaemia can activate microglia through specialized recep- plasticity (Huang and Reichardt, 2001; Issa et al., 2010; tors on their surface called pattern recognition receptors. Miller et al., 1999). The strongest clinical evidence for the Three major families of pattern recognition receptors exist; pathogenic role of cytokines comes from the effects of IFN- Toll-like receptors (TLR), Nod-like receptors (NLR), and α in the treatment of hepatitis C and cancer (Renault et al., RIG1 like receptors, which recognize specific exogenous 1987). IFN-α administration is associated with widespread and endogenous ligands activating specific inflammatory bilateral increases in glucose metabolism in subcortical pathways (Lampron et al., 2013). TLR and NLR can recog- regions including the basal ganglia (Capuron et al., 2007) nize pathogen-associated molecular patterns (PAMPs) dur- and anterior cingulated, which are associated with fatigue ing infection or damage-associated molecular patterns and cognitive effects respectively (Capuron et al., 2005). (DAMPs) such as intracellular protein and non-protein Microglia interact closely with other glial cells, namely products and nucleic acids during neuronal injury. The astrocytes and oligodendrocytes, that play important roles engagement of microglial TLR activates transcription fac- in neural, cognitive, and behavioural functions (Najjar tors such as NF-KB and mitogen-associated protein kinase et al., 2013). Astrocytes maintain BBB integrity, regulate leading to the release of inflammatory cytokines (e.g. synaptic transmission, and are responsible for downregulat- IL-1β, TNF-α, IL-6), chemokines acting as chemoattract- ing harmful inflammation initiated by microglia by activat- ants for other immune cells, reactive oxygen species, nitric ing the Th2 response and D2 receptors. Astrocytes express oxide, and prostanoids by activating the phospholipase A2 TLR and can amplify the CNS innate immune response by and COX-2 pathway. Although microglial activation is an secreting complement components and chemokines. important component of innate immunity serving to protect Astrocytes reduce the effects of excitotoxic glutamate by the CNS from harmful stimuli, under some poorly under- increasing their uptake, and inflammatory responses in the stood circumstances, microglia can become overactivated CNS can compromise this essential astrocyte function, thus and cause neurotoxicity and neurodegeneration. Two pos- amplifying excitotoxicity in the CNS (Zuo et al., 2010; Luo tulated signals are direct stimulation by endogenous pro- and Chen, 2012). Cross-talk between microglia and astro- teins or environmental toxins and neuronal damage-released cytes has been implicated in several neurological condi- DAMPs recognizable by microglial TLR (Block et al., tions, but the details of this interaction are still unclear (Liu 2007; Ransohoff and Brown, 2012). et al., 2011b). Activated microglia express indoleamine 2,3-dioxyge- The third glial cell, the oligodendrocyte, is actively nase, which diverts the tryptophan pathway towards pro- involved in the process of myelination and can downregu- ducing tryptophan catabolites: of these, 3-HK generates late the inflammatory response of microglia by secreting free-radical species that can cause oxidative stress and lipid anti-inflammatory cytokines (Edgar and Sibille, 2012; peroxidation, whereas quinolic acid is associated with glu- Najjar et al., 2013). TNF-α has a direct toxic effect on oli- tamate-induced oxidative damage via NMDA receptor- godendroglia, potentially contributing to apoptosis and mediated, calcium-dependent uncoupling of neuronal demyelination (Miller et al., 2009), and it is inversely mitochondrial electron transport (Berk et al., 2011; Dugan related to the brain-derived neurotrophic factor concentra- et al., 1995; Najjar et al., 2013). The cytokine IL-1β tion, which is known to be reduced in bipolar disorder increases NMDA receptor (NMDAR) contributing to gluta- (Brietzke and Kapczinski, 2008; Kapczinski et al., 2009; mate-mediated neurotoxicity (Viviani et al., 2003). Kaindl Lin, 2009). Oligodendrocytes are particularly susceptible et al. (2012) showed that activation of the NMDAR on to oxidative stress and mitochondrial injury as they contain microglia triggers inflammation and cell death, which in low levels of antioxidant glutathione and express NMDAR turn can further activate microglia and initiate a forward which exposes them to glutamate excitotoxicity (Bradl and feedback loop (Kaindl et al., 2012). Glutamate can activate Lassmann, 2010). The release of reactive oxygen species a Th1 response, and it plays an important role in immu- and nitric oxide not only amplifies the release of pro- nomodulation, particularly the initiation and development inflammatory cytokines, but reactive oxygen species also of T cell-mediated immunity in the periphery and CNS leads to mitochondrial injury by activating oxidative and (Pacheco et al., 2007). Cytokines can upregulate neuronal apoptotic pathways (Lopez-Armada et al., 2013) creating a serotonin transporter activity reducing the strength of sero- vicious cycle of inflammation, oxidative and nitrosative tonin activity at serotonin receptors (Mössner et al., 1998; stress (O&NS), and glutamate excitotoxicity. Furthermore, Zhu et al., 2005). Cytokines such as IL-6 and TNF-α acti- the activation of the O&NS pathways can damage mem- vate the hypothalamic–pituitary–adrenal axis, increasing brane fatty acids and anchorage molecules such as palmitic cortisol levels which can be neurotoxic and may be central acid and myristic acid, causing aberrations in cell signal to the pathogenesis of depressive symptoms and cognitive transduction, cellular architecture, cell differentiation, and deficits (Daban et al., 2005; Dunn, 2000). Elevated cortisol neuroprogression (Maes et al., 2012a).

Australian & New Zealand Journal of Psychiatry, 47(12) Rege and Hodgkinson 1139

The innate immune response can be further amplified by hyperintensities, which can indicate abnormal myelination, a breakdown in the BBB. Leukocytes in the peripheral cir- are found early on in bipolar disorder and play an important culation can bind to the endothelial cells of the BBB role in the pathophysiology of bipolar disorder through a through adhesion molecules such as VCAM-1 and ICAM-1 postulated role of disconnectivity between the frontal cor- and can pass through the BBB due to a loosening of the tex and regions controlling emotional regulation (McIntosh endothelial tight junctions (Rossi et al., 2011). Peripheral et al., 2008; Mahon et al., 2010; Manji et al., 2000). Further cytokines can enter the BBB through areas of the brain that evidence for glial cell loss comes from the levels of S100B, lack the BBB, such as the circumventricular organs which is actively released by astro- and oligodendrocytes. (Dantzer et al., 2000), and the vagus nerve acts as a connec- Significant increases in serum S100B have been observed tion between the peripheral immune system and the brain during episodes of mania and depression, although not in (Gidron et al., 2007). In the CNS, inflammation results in euthymic patients; S100B has therefore been proposed as a the production of inflammatory mediators such as TNF-α, biomarker for mood disorders (Schroeter et al., 2013). IL-6, IL-1β, and arachidonic acid (AA), which can increase Individuals with bipolar disorder show a marked increase BBB permeability (Shalev et al., 2009). Locally produced in the upregulation of pro-apoptotic genes along with a cytokines can also either activate neurons that project to downregulation of antioxidant genes, inducing vulnerabil- specific brain areas or diffuse into the brain parenchyma by ity to apoptosis and oxidative stress-induced damage volume transmission to reach their targets (Dantzer et al., (Benes et al., 2006). The combination of neuronal damage 2000). In summary, microglial activation results in the acti- through the above mechanisms and the suppression of neu- vation of an inflammatory cascade that produces a range of rogenesis (Das and Basu, 2007; Losif et al., 2006) creates downstream mediators that can have the net effect of caus- an environment biased towards neuroprogression that may ing oligodendrocyte apoptosis, BBB damage, mitochon- be implicated in the pathogenesis of symptoms of bipolar drial dysfunction, and neuronal injury. disorder. A detailed explanation of the interaction between Studies have shown evidence of neuroinflammation in cytokines, O&NS stress, mitochondrial dysfunction, apop- individuals with bipolar disorder. Postmortem studies in totic pathways, and neurogenesis is outside the scope of bipolar disorder have shown the presence of excitotoxic this review and we refer readers to the articles by Berk et al. markers and neuroinflammation in the frontal cortex with (2011) and Maes et al. (2011) for further reading. activation of the IL-1 receptor cascade (Rao et al., 2010). Interestingly, the above-described pathways, namely The cytokine IL-1β, which is indicative of microglial acti- mitochondrial dysfunction, neuroinflammation, and oligo- vation, was found to be elevated in the CSF of euthymic dendrocyte abnormalities, show parallels with multiple patients who had a recent manic or hypomanic episode sclerosis (Konradi et al., 2012), which makes it important (Soderlund et al., 2011). The cingulate cortex shows evi- to examine the role of autoreactive T and B cells in the dence of upregulation of the initiating step of the kynure- pathophysiology of bipolar disorder (discussed in the next nine pathway and increased cell adhesion molecule section). Because cytokines play a crucial role in the devel- immunoreactivity, indicating neuroinflammation (Miller opment, differentiation, and regulation of immune cells, the et al., 2006; Thomas et al., 2004). Zanetti et al. (2009), dysregulation of cytokine production is thought to have an using diffusion-tensor imaging, found disruptions in the important role in the development of autoimmune disease ventromedial prefronto-limbic-striatal white matter in (O’Shea et al., 2002). TLR and NLR are an important link bipolar depression, which were hypothesized to result from between innate and adaptive immunity and may be respon- inflammatory causes (Zanetti et al., 2009). Bipolar-type sible for the initiation of the autoimmune response (dis- presentations with mania and hypomania have been cussed later). Moreover O&NS and apoptotic pathways described with IFN-α (Chang et al., 2005; Constant et al., release immunogenic self-epitopes from damaged mem- 2005; Iancu et al., 1997; Malek-Ahmadi, 2001). Elevated branes and proteins that can result in secondary autoim- levels of glutamate, markers of oxidative stress, and mito- mune reactions (Maes et al., 2011). chondrial dysfunction are found in the brains of individuals with bipolar disorder (Andreazza et al., 2008; Clay et al., Peripheral autoimmunity and 2011; Gigante et al., 2012; Hashimoto et al., 2007). bipolar disorder Glial cell abnormalities have been found; however, the data are not consistent and are affected by confounders Autoimmunity is defined as a process whereby an immu- such as medication and phases of illness (Najjar et al., nological response is directed against the body’s self-anti- 2013). Astrocyte involvement is indicated by decreased gens. Autoimmune disease occurs when the immune glial fibrillary acidic protein mRNA in the cingulate cortex reaction overwhelms the normal tolerance checkpoints and (Webster et al., 2005). Reduced oligodendrocyte density, occurs even in the absence of an offending antigen decreased oligodendrocyte gene expression in the frontal (Fairweather, 2007; Goodnow, 2007). A common feature cortex, and white matter involvement have also been of autoimmune diseases is the presence of autoantibodies, detected. (Edgar and Sibille, 2012). White matter which are important markers in the diagnosis and

Australian & New Zealand Journal of Psychiatry, 47(12) 1140 ANZJP Articles classification of autoimmune diseases and can be useful in Thyroid autoimmunity has particularly been shown to psychiatric clinical practice to detect an autoimmune pro- be an independent risk factor for bipolar disorder with no cess. Autoimmune tissue damage can be cell-mediated association with lithium exposure (Haggerty Jr et al., 1990, via T cell activity (cell-mediated immunity), antibody- 1997; Kupka et al., 2002), and it may serve as an endophe- mediated via B cells (humoral immunity), or both (Bellone, notype for bipolar disorder (Vonk et al., 2007). Bipolar dis- 2005; Fairweather, 2007). TLR on the surface of T and B order is associated with organ-specific autoimmunity to the cells are considered to play an important role in the initia- antigens TPO, H/K ATPase, and GAD65, and the level of tion and progression of systemic autoimmune disease TPOAb is inversely correlated with the level of T cell acti- through recognition of exogenous and endogenous anti- vation (Padmos et al., 2004). The female offspring of bipo- gens (Marshak-Rothstein, 2006). DAMPs released during lar disorder patients are more vulnerable to developing mitochondrial apoptosis such as oxidized mitochondrial thyroid autoimmunity, as evidenced by elevated TPOAb DNA bind to NLR activating the inflammatory response titres. However, TPOAb-positive offspring do not show an through caspase-1 activation (Lopez-Armada et al., 2013). increased prevalence of mood disorders compared to T cell-mediated damage to tissues occurs through the TPOAb-negative offspring (Hillegers et al., 2007). Sidhom release of cytotoxic cytokines, prostaglandins, and reac- et al. (2012) have shown that patients with bipolar disorders tive nitrogen and oxygen species. Individuals with bipolar have significantly more autoantibodies compared to people disorder have a bias towards a Th1 pro-inflammatory pro- with other affective or psychotic disorders and non-psychi- file and a reduced number of Treg cells, along with higher atric controls. They concluded that a possible autoimmune levels of senescence-associated cells such as CD8 and activation occurs in at least a subgroup of psychiatric CD25 T cells (do Prado et al., 2012). The T cell system in patients, particularly among those suffering from bipolar bipolar disorder is activated in both symptomatic and disorder. Spivak et al. (1996) found an increased frequency euthymic patients with bipolar disorder (Breunis et al., of antinuclear antibody (ANA) positivity in bipolar patients 2003). Specific alterations in TLR agonist-mediated activ- in comparison to controls, independent of any lithium ther- ity were found in bipolar patients (McKernan et al., 2011). apy. Considering the above evidence, the association is Infections are known to activate TLRs, and antibodies to strongest for thyroid autoimmunity, but its pathophysiology toxoplasma and cytomegalovirus have been found in bipo- is uncertain and may be related to cross-reactivity with glu- lar disorder patients (Tedla et al., 2011). Following TLR- tamate receptors (see later). mediated antigen recognition, GSK3 plays a crucial role in the immune response, and lithium is a GSK3 inhibitor The role of CNS autoimmunity in capable of reducing inflammation (Beurel et al., 2010). bipolar disorder The monocytes of a large proportion of bipolar patients and the offspring of bipolar parents show an inflammatory The cells of the CNS innate immune system interact with T gene expression signature (Padmos et al., 2008) and are cells in the periphery to activate the adaptive immune sys- believed to arise from a shared environmental factor tem. Dendritic cells in the perivascular space and meninges (Padmos et al., 2009). In addition to the enhancement of can activate T cells in the periphery that then traverse the pro-inflammatory monocytes, Tregs are also enhanced in BBB. Once in the CNS, CD4 T cells can be restimulated by bipolar disorder, except in individuals with autoimmune perivascular macrophages and dendritic cells, which act as thyroid disease or bipolar disorder who demonstrate a sig- antigen-presenting cells. T cells release Th1- and or Th2- nificantly reduced percentage of Tregs (Drexhage et al., type cytokines upon antigen recognition by TLRs and inter- 2011). In summary, abnormalities in T cells and cytokines act with microglia and astrocytes to amplify the immune involved in the Th1/Th2 balance show an imbalance response, resulting in the clearance of the offending antigen (Brietzke et al., 2011; Kim et al., 2007) and may represent (Aloisi et al., 2000). underlying T and B cell autoimmunity. The inflamed brain provides a conducive environment B cell-mediated immunity, however, occurs primarily for B cell survival and proliferation resulting in the produc- through antibodies. IL-4 released by Th2 cells activates B tion of antibodies (Corcione et al., 2005). B cells are known cells to produce antibodies. In some individuals who are to cross the CNS and can initiate an autoimmune response susceptible due to a breakdown in tolerance, B cells may against endogenous and exogenous ligands through mecha- produce self-reactive autoantibodies, which constitute the nisms mentioned earlier (Meinl et al., 2006). The produc- hallmark of autoimmune disease. Self-reactive antibodies tion of autoreactive antibodies against neuronal antigens can induce tissue damage by binding to self-tissues (brain reactive antibodies) can interfere with neuronal and activating complement-mediated damage, facilitating transmission, prevent binding of neurotrophic factors such antibody-dependent cell-mediated cytotoxicity (ADCC), as brain-derived neurotrophic factor, and cause direct neu- forming immune complexes, and initiating the comple- ronal injury (Kapadia and Sakic, 2011). For example, ment-induced lysis or removal of cells by phagocytic autoantibodies directed against an epitope on the extracel- immune cells (Fairweather, 2007). lular surface of oligodendrocytes can induce demyelination

Australian & New Zealand Journal of Psychiatry, 47(12) Rege and Hodgkinson 1141 either through activation of complement or through their encephalopathy, have been studied in greater depth by recognition by Fc-receptors of activated macrophages rheumatologists and neurologists. Although case reports of (Bradl and Lassmann, 2010). T and B cell autoimmunity other autoimmune diseases presenting with symptoms of can be triggered through several mechanisms. PAMPs can bipolar disorder exist, we focus on these three disorders due cross-react with self-epitopes through a process of molecu- to their high biological plausibility of being related to the lar mimicry (Chastain and Miller, 2012). Secondly, cell pathophysiology of bipolar symptoms based on evidence of injury in the CNS can result in the release of DAMPs that involvement of the glutamate pathway. Thus, these should can become immunogenic, initiating a T cell autoimmune be considered high on the differential diagnosis list when response against self-antigens (Harris and Fabry, 2012). autoimmunity is suspected in psychiatry. The three autoim- Extracellular mitochondrial DNA is known to be extremely mune disorders are summarized in Table 1. immunogenic and can directly initiate an autoimmune Among the best-known and most well-studied condi- response (Zhang et al., 2010). Cross-reactivity with self- tions is NPSLE. The prevalence of neuropsychiatric mani- antigens can initiate an autoimmune reaction against neu- festations in SLE is estimated to range from 14% to 80% in ronal antigens. For example, a subset of the anti-DNA adults and from 22% to 95% in children (Muscal and Brey, antibody is known to cross-react with the NR2 glutamate 2010; Popescu and Kao, 2011). There have been case receptor (DeGiorgio et al., 2001); elevated serum antibod- reports of NPSLE presenting as bipolar disorder (Alao ies to the NR2 subunit of the glutamate receptor are found et al., 2009; Yeh and Hu, 2007). The most common symp- in the acute phase of mania (Dickerson et al., 2012). Some toms in NPSLE include the following: cognitive dysfunc- DAMPs, such as S100B, extracellular nucleotides, and tion (75–80%), mood disorders (69–74%), headache extracellular matrix components of basement membrane (39–61%), seizures (8–18%), cerebrovascular disease (2– are plausible candidates in the initiation of autoimmune 8%), psychosis (3–5%), cranial neuropathy (1.5–2.1%), response. Furthermore, microscopic particles have been and movement disorders (1%). These symptoms indicate found in the CSF of individuals with bipolar disorder and that NPSLE may present to psychiatrists first (Popescu and only rarely in controls. It is unclear whether these particles Kao, 2011). Cytokines and chemokines play key roles in represent DAMPs, and further research is required to clar- the pathogenesis of NPSLE (Okamoto et al., 2010). A key ify this (Johansson et al., 2012). Kapadia and Sakic (2011) effector mechanism in NPSLE in the development of cog- have integrated the CNS innate and adaptive immune sys- nitive dysfunction and mood disorders may be the gluta- tem mechanisms by proposing two phases, the inflamma- matergic pathway through the NMDA receptors situated in tory phase, which is dominated by innate immunity and the hippocampus, frontal regions, and limbic system (Mak leads to functional damage, followed by the autoimmune et al., 2009). dsDNA antibody is an important antibody in phase, which is responsible for structural damage such as this respect due to its cross-reactivity with the NR2 gluta- neurodegeneration and atrophy. CNS T and B cell autoim- mate receptor (DeGiorgio et al., 2001). The pathogenesis of munity is an underexplored area in bipolar disorder. It NPSLE is multifactorial and is shown in Figure 1. should be noted that endogenous protective regulatory sig- The diagnosis of neuropsychiatric lupus in clinical prac- nals, such as Treg cells and B cell-mediated immunoregula- tice is a contentious issue amongst psychiatrists, rheuma- tion, exist in the brain to prevent autoimmune responses tologists, and other caregivers. Standard laboratory testing and that the dysregulation of such mechanisms may be and imaging studies may not always detect active brain dis- responsible for initiating and promoting autoimmune ease or static damage (Wright, 2010). Thus, it is important responses (Block et al., 2007; Goverman, 2009). for psychiatrists to be aware of the limitations in diagnostic criteria and the potential management issues they face. There is no single diagnostic test for SLE, and the American Autoimmune disorders and bipolar College of Rheumatology criteria are intended for classifi- disorder: focus on neuropsychiatric cation rather than diagnosis (Hughes, 1998). ANA and lupus erythematosus, anti-NMDA dsDNA antibody are sensitive and specific serological encephalitis, and Hashimoto’s markers, respectively, for SLE. The application of the encephalopathy NPSLE criteria in psychiatry is limited by the requirement of a temporal relationship between SLE and a psychiatric A large Danish cohort study showed that autoimmune pro- disorder (SLE before neuropsychiatric presentation); this cesses precede the onset of bipolar disorder (Eaton et al., contradicts evidence showing that the brain may be affected 2010). Although research on the link between autoimmune early in SLE with primary neuropsychiatric presentations, diseases and psychiatric disorders is at a relatively early even before a diagnosis of SLE is made, and neither a nor- stage, autoimmune diseases, such as autoimmune synaptic mal erythrocyte sedimentation rate nor negative serology encephalitis, neuropsychiatric systemic lupus erythemato- excludes CNS lupus (Joseph et al., 2007; Petri et al., 2008). sus (NPSLE), and encephalopathy associated with autoim- Moreover, NPSLE manifestations have been found to be mune thyroiditis (EAAT), particularly Hashimoto’s negatively correlated with systemic manifestations such as

Australian & New Zealand Journal of Psychiatry, 47(12) 1142 ANZJP Articles

Table 1. Summary of important autoimmune disorders presenting with psychiatric symptoms.

Condition Clinical features Investigations Pathogenesis Treatment

Anti-NMDA 80% women Antineuronal antibodies Anti-NMDA IV methylprednisone Encephalitis antibodies against the NR1 subunit

Other antibodies against synaptic antigens: Anti-Hu, Anti-Ma Anti-CRMP-5 and CV2 Anti-VgKC Anti-AMPA Anti-GABA-B Any age group MRI: T2 or FLAIR signal in Immunosuppressants medial temporal lobes (15%); normal in >50% Symptoms preceded EEG: Non-specific slow, IV IgG by prodromal viral disorganized activity, illness or URTI sometimes with seizure activity Psychosis, memory CSF: lymphocytic Cyclophosphamide deficits, confusion, pleiocytosis (80%) and ritumixab dyskinesia, seizures, autonomic instability Associated with tumour in some casesa

NPSLE Female:male ratio 9:1 ANA, dsDNA antibody See Figure 2 Psychotropics Women in Antineuronal antibodies, Steroids childbearing years anti-phospholipid antibodies Cognitive dysfunction EEG: non-specific generalized NSAIDs or focal slowing/seizures or seizure-like activity Mood disorder MRI: multiple discrete Hydroxychloroquine white-matter lesions in periventricular and subcortical white matter (40–80%) Headache FDG PET: parieto- Immunosuppressants occipital white matter hypometabolism (60–80%) Seizures SPECT: areas of Antiplatelet agents hypoperfusion and anticoagulation CVD Psychosis Cranial neuropathy Movement disorder Features of SLE

Encephalopathy Fifth and sixth decade Anti-TPO Autoimmune IV methylprednisone associated with of life Anti-thyroglobulin (TgAb) cerebral vasculitis (1 g/kg) autoimmune thyroiditis 80% female patients CSF: lymphocytic Antibodies against Oral prednisone (Hashimoto’s Cognitive impairment pleiocytosis (80%) amino terminus of (1–2 mg/kg) encephalopathy) Seizures EEG: generalized slowing/ alpha enolase (NAE) Immunosuppressive FIRDA/focal slow waves/ Intrathecal thyroid drugs epileptiform discharges antibodies Good response to Global cerebral steroids hypoperfusion (Continued)

Australian & New Zealand Journal of Psychiatry, 47(12) Rege and Hodgkinson 1143

Table 1. (Continued)

Condition Clinical features Investigations Pathogenesis Treatment

Behavioural disorders MRI: normal in 50% of cases, Anti-GluRε2 T2 high-intensity signal antibodies

Myoclonus Ataxia Dysphasia Aphasia Confusion Tremor Psychosis Headache aOver 50% of cases are not associated with a neoplasm. CSF, cerebrospinal fluid; CVD, cardiovascular disease; EEG, electroencephalography; FDG PET, fluorodeoxyglucose positron emission tomography; MRI, magnetic resonance imaging; NSAID, nonsteroidal anti-inflammatory drug; SPECT, single-photon emission computed tomography Source: Castillo et al. (2006); de Hollanda (2011); Kayser et al. (2010); Popescu and Kao (2011); and Brey and Muscal (2010).

Figure 1. The pathogenic mechanism of autoantibodies is related to the breakdown of the blood–brain barrier and CSF autoantibodies forming and binding to the cell antigens that are released by neurocytotoxic antibodies (e.g. anti-ribosomal P, anti-NR2), which form immune complexes and stimulate production of IFN-α and pro-inflammatory cytokines and chemokines (Fragoso-Loyo et al., 2007; Santer et al., 2009). IFN-α is thought to be the effector mechanism of cognitive and mood effects in NPSLE. Thus, serum antibodies of SLE (antinuclear antibody and dsDNA antibody) may not be reliable markers of neuropsychiatric disease, as there is a lack of correlation between serum autoantibodies and NPSLE manifestations, and neuropsychiatric manifestations may be mediated by alternate antibodies, such as NR2 glutamate-receptor antibodies that cross-react with anti- DNA antibodies (Arinuma et al., 2008; DeGiorgio et al., 2001; Omdal et al., 2005).

joint and skin involvement in children and adults (Harel severe disease and a longer duration of disease and do not et al., 2006; Karassa et al., 2000), and the American College reflect clinical diagnoses as assigned by lupus experts of Rheumatology criteria may be biased towards more (Wallace and Hahn, 2006). Thus, clinical diagnostic

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Table 2. Clinical indicators that should raise suspicion of autoimmunity in practice.

Neuropsychiatric Others

Treatment resistance or progression despite Arthritis therapeutic doses of psychotropics

Atypical psychiatric presentations Facial erythematous rash/discoid rash/photosensitivity

Stroke/transient ischaemic attack Kidney disease

Headache/migraine Recurrent miscarriages

Cognitive dysfunction Hypo/hyperthyroidism

Movement disorder (chorea, dystonia, Family history of autoimmunity Parkinsonism, catatonia)

Seizures Viral prodrome

Fluctuating presentation Significantly elevated ANA and dsDNA antibody

Acute behavioural/personality change T2 and FLAIR signal abnormalities on MRI

Neuropathy Abnormal EEG

A number of the above symptoms should Elevated ANA is useful in confirming suspicions, but a negative ANA or prompt serological testing and investigations for dsDNA antibody does not rule out autoimmunity or NPSLE. The test autoimmune disease. The symptoms could be for ANAs has a very high diagnostic sensitivity, such that it is considered present at any time in a person’s life; hence, a the best test for the screening for systemic autoimmune diseases but medical history (current and past) and medical caution is to be exercised and recommendations are that tests to detect examination are important autoantibodies are performed only when a consistent clinical suspicion of autoimmune disease is present (Tozzoli et al., 2002)

ANA, antinuclear antibody. impressions in NPSLE must be based on the combined use with anti-NMDA encephalitis have been described, and 75% of immunoserological testing, functional and/or structural present initially to psychiatrists (Kayser et al., 2010). The neuroimaging, and standardized neurological, rheumato- antibody in anti-NMDA encephalitis specifically recognizes logical, psychiatric, and neuropsychological assessments the NR1 subunit of the NMDA receptor, which is present in (Hermosillo-Romo and Brey, 2002). These findings show all NMDA receptors (Dalmau et al., 2008). In contrast, the that the current criteria for NPSLE diagnosis and their gen- antineuronal antibodies in NPSLE recognize the NR2A and eralizability to psychiatric patients should be examined in NR2B subunits of the NMDA receptor, which are highly con- view of the high degree of morbidity and mortality associ- centrated in the hippocampus (Kayser and Dalmau, 2011). ated with NPSLE (Monov and Monova, 2008). The major These differences in location and antigenic targets may histocompatability complex located on chromosome 6 pro- explain the difference in presentation between NPSLE and vides further support for the association between bipolar anti-NMDA encephalitis. Recently, antineuronal antibodies, disorder and NPSLE: the genes in this region have been which are characteristic of synaptic encephalitis, have been implicated in bipolar disorder and provide a strong genetic considered important biomarkers in NPSLE (Gorman, 2011). association with a range of autoimmune disorders, particu- EAAT is the third important differential. In the context larly SLE (Harley, 2002; International Schizophrenia of encephalopathy, anti-TPO antibodies are used to diag- Consortium et al., 2009; Jonsen et al., 2004). nose Hashimoto’s encephalopathy (Mocellin et al., 2007). The identification of encephalitis associated with antibod- Reports exist of Hashimoto’s encephalopathy presenting ies against cell surface and synaptic antigens has had a sub- with depression, mania, and cognitive dysfunction stantial impact in neuropsychiatry. Classically, encephalitis (Bochetta et al., 2007; Canelo-Aybar et al., 2011; Liu et al., due to synaptic antibodies evolves over days to weeks and 2011a; Mussig et al., 2005). This disorder is also termed includes psychiatric manifestations as diverse as irritability, steroid-responsive EAAT due to its often-dramatic response mood disturbance, hallucinations, and personality distur- to steroids (Castillo et al., 2006). Despite concerns regard- bances. Further neurocognitive changes occur in the form of ing steroid use in psychosis, a good response to steroids has short-term memory loss, sleep disturbances, and seizures. been obtained in psychosis associated with autoimmune Anti-NMDA encephalitis is of particular relevance to psy- thyroiditis, implying an immunological pathogenesis chiatrists due to its clinical presentation. Over 200 patients (Arrojo et al., 2007; Gómez-Bernal et al., 2007). A recent

Australian & New Zealand Journal of Psychiatry, 47(12) Rege and Hodgkinson 1145 study showed that anti-GluRε2 antibodies may be associ- Future research and implications ated with the neuropsychiatric manifestations of psychiat- for clinical practice ric patients with antithyroid antibodies (Chiba et al., 2012). The treatment response to immunomodulation in these A limitation in the existing literature examining cytokines patients has not been studied. and bipolar disorder is the cross-sectional nature of the stud- In Table 2, we present a list of clinical features based on ies. It is unclear if the cytokine dysfunction represents a true a review of the important autoimmune conditions described causal mechanism in the pathophysiology of bipolar disor- above that can help increase the detection of autoimmunity der, is an epiphenomenona, or is related to medication in psychiatry. Although this list has not yet been validated (Langan and McDonald, 2009). It may also represent under- to any degree, it may help clinicians to suspect autoimmun- lying T and B cell autoimmunity. It is also too early to com- ity and form a basis for further research. The detailed treatment on the relationship of autoimmunity with the ment of each disorder is outside the scope of the article and pathophysiology of bipolar disorder. Identifying specific includes a combination of psychotropics, corticosteroids, autoantibodies in varying phases of the illness may be one and immunosuppressants that is summarized in Table 1. way forward (antibodies to 5-HT and anchorage molecules Thus, NPSLE, some forms of autoimmune encephalitides, as found in depression; Maes et al., 2011, 2012b). Antibodies and some subsets of bipolar disorder presentations may have against NMDARs merit further investigation in bipolar dis- common underlying pathophysiological mechanisms. order. Future research should include autoantibodies and inflammatory markers as biomarkers in addition to clinical The role of stress and its interaction with features and neuroimaging with the aim of stratifying psy- the immune system chiatric presentations. This is in line with proposals by Kapur et al. (2012) for “stratified psychiatry”, which will A stressful event is often associated with bipolar disorder improve clinical outcomes across conventional diagnostic presentations. There are no specific studies examining the boundaries. With the advent of neuroimaging techniques role of stress, immune dysregulation, and autoimmunity in such as two-/multiphoton and fluorescence microscopy, bipolar disorder, and we discuss this association in general existing nuclear medicine techniques with radiolabelled terms. The link between stress and mood disorders is well ligands for cells involved in neuroinflammation, and tech- recognized, with corticotrophin-releasing hormone playing niques to visualize T cell movement and migration, further an important role in the pathophysiology (Stout and advances will result in an improved understanding of the Nemeroff, 1994). Retrospective studies in autoimmune dis- role of neuroinflammation in psychiatric disorders. eases have found that up to 80% of patients report uncom- Current research examining the link between autoim- mon emotional stress before disease onset (Stojanovich and mune diseases and psychiatry may be susceptible to referral Marisavljevich, 2008). Psychosocial stressors activate cor- and spectrum bias. Longitudinal prospective cohort studies ticotrophin-releasing hormone and the sympathetic nervous are required to establish the pathogenesis of the neuropsychi- system, increasing NF-KB DNA binding in inflammatory atric autoimmune disease process and evaluate the interven- cells and resulting in the release of cytokines that act tions that are appropriate. There is a case for multispecialty through the pathways described earlier. Pro-inflammatory collaboration in research projects due to the multisystem cytokines then induce cortisol release, which aims to involvement of autoimmune diseases. In clinical practice, decrease the inflammatory response. This pathway is down- the diagnosis of autoimmune encephalopathy requires a high regulated in chronic stress, resulting in an imbalance index of clinical suspicion, as tests including serology, EEG, between pro-inflammatory and anti-inflammatory CSF, and MRI can be normal and do not exclude an autoim- cytokines (Miller et al., 2009). Furthermore, there is evi- mune pathology. Psychiatrists should pay particular attention dence that brief naturalistic stressors, such as academic to the milder incomplete cases of anti-NMDA encephalitis exams, potentiate a shift towards a Th2 response, whereas (formes frustes), which may continue to be treated as psychi- chronic stress reduces both Th1 and Th2 responses atric disorders (Dalmau et al., 2011). Clues to autoimmune (Plotnikoff, 2007; Segerstrom and Miller, 2004). Figure 2 encephalopathies often lie in the longitudinal history. synthesizes this evidence to propose a hypothesis of the Movement disorders, cognitive dysfunction, and fluctuating interaction between stress/trauma, cytokines, the hypotha- cognition are common in all three autoimmune encephalopa- lamic–pituitary–adrenal axis, autoimmunity, and the brain thies and can be attributed incorrectly to antipsychotic medi- in the pathogenesis of psychiatric symptoms. The model is cation, thus creating a protopathic bias. A detailed medical complicated by other triggers, such as physical CNS injury evaluation (history and examination), cognitive examina- and infections, both of which can activate autoimmunity. tion, case-note review, and corroborative history taking from This model can be extrapolated to other psychiatric disor- the family are important in psychiatric evaluations, particu- ders. We refer readers to Plotnikoff (2007) and Segerstrom larly in atypical presentations characterized by a non- and Miller (2004) for a more detailed explanation on the response or poor response to psychotropics. Based on advice role of stress and the immune system. by Neuwelt and Young (2009), the management of

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Figure 2. The role of stress and its interaction with the immune system. Stress and trauma lead to activation of cytokine and cortisol release which lead to an adaptive T cell response to external or internal antigens (Segerstrom and Miller, 2004). Cortisol acts by reducing inflammatory tissue damage due to inflammatory cytokines. The cortisol release is modulated by the hypothalamic–pituitary–adrenal axis feedback mechanism to avoid prolonged cortisol release. In chronic stress, however, prolonged elevated cortisol release leads to downregulation of cortisol receptors on T lymphocytes resulting in unrestricted tissue damage and amplification of the immune response resulting in autoimmunity in susceptible individuals (Cohen et al., 2012). This susceptibility is governed by genes, environmental factors, or hormonal factors. The activation of autoimmunity and cytokine release can result in endothelial cell damage at the level of the blood–brain barrier resulting in passage of cytokines through the blood–brain barrier. Cytokines then act on the brain though various mechanisms resulting in the genesis of psychiatric symptomatology. SERT, serotonin transporter; IDO, indoleamine 2,3-dioxygenase.

autoimmune encephalopathies requires a team approach, From a treatment perspective, the consideration of the including a rheumatologist, neurologist, neuroimmunologist, immune hypothesis opens up a new avenue for research into psychiatrist, neuropsychologist, oncologist, and primary- the role of immunomodulators in psychiatry. Although this care physician, to formulate a proper diagnosis and treatment review cannot make conclusive treatment recommenda- plan for the management of NPSLE. tions, there is a case for an empirical trial of

Australian & New Zealand Journal of Psychiatry, 47(12) Rege and Hodgkinson 1147 steroids in suspected cases of immune-related psychiatric underlying somatic symptoms in PTSD through the encephalopathy after excluding infections, as in cases of cytokine pathway (Aerni et al., 2004; Rohleder et al., 2009). limbic encephalitis and steroid-responsive EAAT (Bataller Traumatic brain and spinal injuries are associated with anti- et al., 2007; Castillo et al., 2006). It is important that the body production, which is responsible for a range of psychiatrist be familiar with steroid administration and its somatic symptoms that cannot be explained purely by neu- side effects. Knight et al. (2007) have noted that concerns rological injury (Ankeny and Popovich, 2010). about corticosteroids in psychiatry are not well founded and are based primarily on anecdotal evidence. The prescription of psychotropics in the context of organic brain disease can Conclusions increase morbidity, mortality, and the risk of Neuroleptic The link between immune dysregulation, autoimmunity, Malignant Syndrome (NMS) (Adnet et al., 2000; Maat and psychiatric illness may be closer than previously et al., 2012), notwithstanding the morbidity and mortality thought. The identification of aetiological markers to guide from untreated conditions such as NPSLE (Yu et al., 2006) treatment has largely eluded psychiatrists. With the advent and autoimmune synaptic encephalitis. Thus, a careful, of sophisticated neuroimaging techniques and immunologi- individualized risk–benefit analysis is required. Among psy- cal markers, psychiatrists will be able to identify subsets of chotropics, lithium and clozapine (used in certain treatment- disorders that have an immunological basis. This review resistant illnesses) have immunosuppressive properties adds to the increasing body of evidence suggesting that (Beurel et al., 2010; Boufidou et al., 2004; Knight et al., immune dysregulation, neuroinflammation, and autoim- 2007; Maes et al., 2007) that possibly contribute to their munity may play an important role in psychiatric disorders. superiority in treatment-resistant cases; however, their use NPSLE, anti-NMDA encephalitis, and EAAT are important in autoimmune encephalopathies has not been evaluated. differentials for the psychiatrist to consider when suspecting The use of anti-inflammatory medications is also known to autoimmune encephalopathy. Even if the autoimmune dis- restore adult hippocampal neurogenesis and thus has the ease is not directly aetiologically related to the psychiatric potential to improve cognitive deficits (Monje et al., 2003). presentation, its detection is important due to the high mor- Existing cytokine inhibitors (anti-TNF-α), such as etaner- bidity and mortality associated with autoimmune diseases. cept, adalimumab, and infliximab, are used in the manage- Early intervention could result in a significant decrease in ment of rheumatoid arthritis and psoriasis and have been morbidity for patients and in cost savings for services by shown to both relieve the symptoms of psoriasis and preventing multisystem involvement in the future. improve affective, somatic, and cognitive functions In the end, it is clear that if the understanding of a dis- (Soczynska et al., 2009; Tyring et al., 2006), but they have ease is to be furthered in the 21st century, the current not been evaluated in primary psychiatric presentations. The Cartesian mind–body dichotomy is an untenable paradigm, role of smoking cessation and addressing alcohol misuse just as Plato discovered over 2000 years ago. should not be overlooked, as smoking is a direct contribu- tory factor to the passage of cytokines through the BBB, and Acknowledgements alcohol exerts pro-apoptotic effects on neuronal cells (Valles et al., 2004). Omega-3 fatty acids, N-acetyl cysteine, statins, We would like to thank Professor David Castle and Professor coenzyme Q10, lipoic acid, curcuma, and TNF inhibitors Philip Boyce for their criticism and comments in the preparation of this manuscript. are potential therapeutic neuroprotective factors acting on inflammatory, apoptotic, and oxidative pathways (Berk et al., 2011). Future treatments could include medications Funding that act on neuroinflammatory pathways. This research received no specific grant from any funding agency The roles of stress and trauma in immunity and autoim- in the public, commercial, or not-for-profit sectors. munity offer new opportunities for research in patients with borderline personality disorder (BPD), post-traumatic Declaration of interest stress disorder (PTSD), and traumatic brain injury. In BPD, SR is a founding trainer at Psych Scene, a company providing the links with thyroid antibodies (Geracioti et al., 2003), educational courses for psychiatry exams. SJH reports no conflict increased pro-inflammatory cytokines (Kahl et al., 2006) of interest. The authors alone are responsible for the content and and high rates (30–84%) of diffuse slow-wave and spike- writing of the paper. wave EEG abnormalities (Boutros et al., 2003) raise the question of whether BPD is a form of chronic subacute References encephalopathy that is related to autoimmunity. In PTSD, cortisol treatment has been proposed to ameliorate the Adnet P, Lestavel P and Krivosic-Horber R (2000) Neuroleptic malignant syndrome. British Journal of Anaesthesia 85: 129–135. intensity of intrusive memories and might also be useful in Aerni A, Traber R, Hock C, et al. (2004) Low-dose cortisol for symp- preventing low-grade systemic inflammation, which in toms of posttraumatic stress disorder. American Journal of Psychiatry turn, is discussed as a pathophysiological mechanism 161:1488–1490.

Australian & New Zealand Journal of Psychiatry, 47(12) 1148 ANZJP Articles

Alao AO, Chlebowski S and Chung C (2009) Neuropsychiatric systemic Castillo P, Woodruff B, Caselli R, et al. (2006) Steroid-responsive lupus erythematosus presenting as bipolar I disorder with catatonic encephalopathy associated with autoimmune thyroiditis. Archives of features. Psychosomatics 50: 543–547. Neurology 63: 197–202. Aloisi F, Ria F and Adorini L (2000) Regulation of T-cell responses by Chang CC, Shiah IS, Chen CL, et al. (2005) Bipolar disorder induced by CNS antigen-presenting cells: different roles for microglia and astro- resuming interferon-alpha treatment in a patient with chronic hepatitis B. cytes. Immunology Today 21: 141–147. Journal of Medical Sciences 25: 101–104. Andreazza AC, Kauer-Sant’Anna M, Frey BN, et al. (2008) Oxidative Chastain EM and Miller SD (2012) Molecular mimicry as an inducing stress markers in bipolar disorder: a meta-analysis. Journal of trigger for CNS autoimmune demyelinating disease. Immunological Affective Disorders 111: 135–144. Reviews 245: 227–238. Ankeny DP and Popovich PG (2010) B cells and autoantibodies: complex Chiba Y, Katsuse O, Takahashi Y, et al. (2012) Anti-glutamate receptor ε2 roles in CNS injury. Trends in Immunology 31: 332–338. antibodies in psychiatric patients with anti-thyroid autoantibodies – a Arinuma Y, Yanagida T and Hirohata S (2008) Association of cerebrospinal prevalence study in Japan. Neuroscience Letters 534: 217–222. fluid anti-NR2 glutamate receptor antibodies with diffuse neuropsychiatric Clay HB, Sillivan S and Konradi C (2011) Mitochondrial dysfunction systemic lupus erythematosus. Arthritis and Rheumatism 58: 1130–1135. and pathology in bipolar disorder and schizophrenia. International Arrojo M, Perez-Rodriguez MM, Mota M, et al. (2007) Psychiatric pres- Journal of Developmental Neuroscience 29: 311–324. entation of Hashimoto’s encephalopathy. Psychosomatic Medicine Cohen S, Janicki-Deverts D, Doyle WJ, et al. (2012) Chronic stress, glucocor- 69: 200–201. ticoid receptor resistance, inflammation, and disease risk. Proceedings Bataller L, Kleopa KA, Wu GF, et al. (2007) Autoimmune limbic enceph- of the National Academy of Sciences, USA 109: 5995–5999. alitis in 39 patients: immunophenotypes and outcomes. Journal of Constant A, Castera L, Dantzer R, et al. (2005) Mood alterations during Neurology, Neurosurgery and Psychiatry 78: 381–385. interferon-alpha therapy in patients with chronic hepatitis C: evidence Bellone M (2005) Autoimmune disease: pathogenesis. Hoboken, NJ: for an overlap between manic/hypomanic and depressive symptoms. Wiley. Journal of Clinical Psychiatry 66: 1050–1057. Benes FM, Matzilevich D, Burke RE, et al. (2006) The expression of proa- Corcione A, Aloisi F, Serafini B, et al. (2005) B-cell differentiation in the poptosis genes is increased in bipolar disorder, but not in schizophre- CNS of patients with multiple sclerosis. Autoimmunity Reviews 4: nia. Molecular Psychiatry 11: 241–251. 549–554. Berk M, Kapczinski F, Andreazza AC, et al. (2011) Pathways underlying Daban C, Vieta E, Mackin P, et al. (2005) Hypothalamic-pituitary-adrenal neuroprogression in bipolar disorder: focus on inflammation, oxida- axis and bipolar disorder. Psychiatric Clinics of North America 28: tive stress and neurotrophic factors. Neuroscience and Biobehavioral 469–480. Reviews 35: 804–817. Dalmau J, Gleichman AJ, Hughes EG, et al. (2008) Anti-NMDA-receptor Beurel E, Michalek SM and Jope RS (2010) Innate and adaptive immune encephalitis: case series and analysis of the effects of antibodies. responses regulated by glycogen synthase kinase-3 (GSK3). Trends in Lancet Neurology 7: 1091–1098. Immunology 31: 24–31. Dalmau J, Lancaster E, Martinez-Hernandez E, et al. (2011) Clinical expe- Block ML, Zecca L and Hong JS (2007) Microglia-mediated neuro- rience and laboratory investigations in patients with anti-NMDAR toxicity: uncovering the molecular mechanisms. Nature Reviews encephalitis. Lancet Neurology 10: 63–74. Neuroscience 8: 57–69. Dantzer R, Konsman JP, Bluthé RM, et al. (2000) Neural and humoral Bochetta A, Tamburini G, Cavolina P, et al. (2007) Affective psychosis, pathways of communication from the immune system to the brain: Hashimoto’s thyroiditis, and brain perfusion abnormalities: case parallel or convergent? Autonomic Neuroscience 85: 60–65. report. Clinical Practice and Epidemiology in Mental Health 3: 31. Das S and Basu A (2007) Inflammation: a new candidate in modulating Boufidou F, Nikolaou C, Alevizos B, et al. (2004) Cytokine production in adult neurogenesis. Journal of Neuroscience Research 86: 1199–1208. bipolar affective disorder patients under lithium treatment. Journal of Davison K (2012) Autoimmunity in psychiatry. British Journal of Affective Disorders 82: 309–313. Psychiatry 200: 353–355. Boutros NN, Torello M and McGlashan TH (2003) Electrophysiological DeGiorgio LA, Konstantinov KN, Lee SC, et al. (2001) A subset of lupus aberrations in borderline personality disorder: state of the evidence. anti-DNA antibodies cross-reacts with the NR2 glutamate receptor in Journal of Neuropsychiatry and Clinical Neurosciences 15, 145–154. systemic lupus erythematosus. Nature Medicine 7: 1189–1193. Bradl M and Lassmann H (2010) Oligodendrocytes: biology and pathol- Dickerson F, Stallings C, Vaughan C, et al. (2012) Antibodies to the gluta- ogy. Acta Neuropathologica 119: 37–53. mate receptor in mania. Bipolar Disorders 14: 547–553. Breunis MN, Kupka RW, Nolen WA, et al. (2003) High numbers of cir- do Prado CH, Rizzo LB, Wieck A, et al. (2012) Reduced regulatory T cells culating activated T cells and raised levels of serum IL-2 receptor in are associated with higher levels of Th1/TH17 cytokines and acti- bipolar disorder. Biological Psychiatry 53: 157–165. vated MAPK in type 1 bipolar disorder. Psychoneuroendocrinology Brietzke E and Kapczinski F (2008) TNF-α as a molecular target in bipo- 38: 667–676. lar disorder. Progress in Neuro-Psychopharmacology and Biological Drexhage RC, Hoogenboezem TH, Versnel MA, et al. (2011) The activa- Psychiatry 32: 1355–1361. tion of monocyte and T cell networks in patients with bipolar disorder. Brietzke E, Kauer-Sant’Anna M, Teixeira AL, et al. (2009) Abnormalities Brain, Behavior and immunity 25: 1206–1213. in serum chemokine levels in euthymic patients with bipolar disorder. Dugan LL, Sensi SL, Canzoniero LM, et al. (1995) Mitochondrial produc- Brain, Behavior and Immunity 23: 1079–1082. tion of reactive oxygen species in cortical neurons following exposure Brietzke E, Stabellini R, Grassis-Oliveira R, et al. (2011) Cytokines in to N-methyl-D-aspartate. Journal of Neuroscience 15: 6377–6388. bipolar disorder: recent findings, deleterious effects but promise for Dunn AJ (2000) Cytokine activation of the HPA axis. Annals of the New future therapeutics. CNS Spectrums 16: 157–168. York Academy of Sciences 917: 608–617. Canelo-Aybar C, Loja-Oropeza D, Cuadra-Urteaga J, et al. (2011) Eaton WW, Pedersen MG, Nielsen PR, et al. (2010) Autoimmune diseases, Hashimoto’s encephalopathy presenting with neurocognitive symp- bipolar disorder, and non-affective psychosis. Bipolar Disorders 12: toms: a case report. Journal of Medical Case Reports 4, 337. 638–646. Capuron L, Pagnoni G, Demetrashvili M, et al. (2005) Anterior cingu- Edgar N and Sibille E (2012) A putative functional role for oligodendro- late activation and error processing during interferon-alpha treatment. cytes in mood regulation. Translational psychiatry 2: e109. Biological Psychiatry 58: 190–196. Fairweather D (2007) Autoimmune disease: mechanisms. Hoboken, NJ: Capuron L, Pagnoni G, Demetrashvili MF, et al. (2007) Basal ganglia Wiley. hypermetabolism and symptoms of fatigue during interferon-alpha Fan X, Goff DC and Henderson DC (2007) Inflammation and schizophre- therapy. Neuropsychopharmacology 32: 2384–2392. nia. Expert Review of Neurotherapeutics 7: 789–796.

Australian & New Zealand Journal of Psychiatry, 47(12) Rege and Hodgkinson 1149

Fearon DT and Locksley RM (1996) The instructive role of innate immu- Jonsen A, Bengtsson AA, Sturfelt G, et al. (2004) Analysis of HLA DR, nity in the acquired immune response. Science 272: 50–53. HLA DQ, C4A, FcgammaRIIa, FcgammaRIIIa, MBL, and IL-1Ra Fragoso-Loyo H, Richaud-Patin Y, Orozco-Narvaez A, et al. (2007) allelic variants in Caucasian systemic lupus erythematosus patients Interleukin-6 and chemokines in the neuropsychiatric manifesta- suggests an effect of the combined FcgammaRIIa R/R and IL-1Ra 2/2 tions of systemic lupus erythematosus. Arthritis and Rheumatism 56: genotypes on disease susceptibility. Arthritis Research and Therapy 1242–1250. 6: R557–R562. Geracioti TD Jr, Kling MA, Post RM, et al. (2003) Antithyroid antibody- Joseph FG, Lammie GA and Scolding NJ (2007) CNS lupus: a study of 41 linked symptoms in borderline personality disorder. Endocrine 21: patients. Neurology 69: 644–654. 153–158. Kahl KG, Bens S, Ziegler K, et al. (2006) Cortisol, the cortisol-dehydroe- Gidron Y, Kupper N, Kwaijtaal M, et al. (2007) Vagus-brain communica- piandrosterone ratio, and pro-inflammatory cytokines in patients with tion in atherosclerosis-related inflammation: a neuroimmunomodula- current major depressive disorder comorbid with borderline personal- tion perspective of CAD. Atherosclerosis 195: e1–e9. ity disorder. Biological Psychiatry 59: 667–671. Gigante AD, Bond DJ, Lafer B, et al. (2012) Brain glutamate levels meas- Kaindl AM, Degos V, Peineau S, et al. (2012) Activation of microglial ured by magnetic resonance spectroscopy in patients with bipolar dis- N-methyl-D-aspartate receptors triggers inflammation and neuronal order: a meta-analysis. Bipolar Disorders 14: 478–487. cell death in the developing and mature brain. Annals of Neurology Gómez-Bernal GJ, Reboreda A, Romero F, et al. (2007) A case of 72: 536–549. Hashimoto’s encephalopathy manifesting as psychosis. Primary Care Kapadia M and Sakic B (2011) Autoimmune and inflammatory mecha- Companion to the Journal of Clinical Psychiatry 9: 318–319. nisms of CNS damage. Progress in Neurobiology 95: 301–333. Goodnow CC (2007) Multistep pathogenesis of autoimmune disease. Cell Kapczinski F, Dias VV, Frey BN, et al. (2009) Brain-derived neurotrophic 130: 25–35. factor in bipolar disorder: beyond trait and state: comment on “Decreased Gorman M (2011) Will anti-neuronal antibody biomarkers make neu- levels of serum brain-derived neurotrophic factor in both depressed and ropsychiatric systemic lupus erythematosus no longer a diagnosis of euthymic patients with unipolar depression and in euthymic patients exclusion? Developmental Medicine and Child Neurology 53: 483. with bipolar I and II disorders”. Bipolar Disorders 11: 221–222. Goverman J (2009) Autoimmune T cell responses in the central nervous Kapur S, Phillips AG and Insel TR. (2012) Why has it taken so long for system. Nature Reviews Immunology 9: 393–407. biological psychiatry to develop clinical tests and what to do about it. Haggerty JJ Jr, Evans DL, Golden RN, et al. (1990) The presence of Molecular Psychiatry 17: 1174–1179. antithyroid antibodies in patients with affective and nonaffective psy- Karassa FB, Ioannidis JP, Touloumi G, et al. (2000) Risk factors for cen- chiatric disorders. Biological Psychiatry 27: 51–60. tral nervous system involvement in systemic lupus erythematosus. Haggerty JJ Jr, Silva SG, Marquardt M, et al. (1997) Prevalence of QJM: Monthly Journal of the Association of Physicians 93: 169–174. antithyroid antibodies in mood disorders. Depression and Anxiety 5: Kauer-Sant’Anna M, Kapczinski F, Andreazza AC, et al. (2009) Brain- 91–96. derived neurotrophic factor and inflammatory markers in patients Harel L, Sandborg C, Lee T, et al. (2006) Neuropsychiatric manifesta- with early- vs. late-stage bipolar disorder. International Journal of tions in pediatric systemic lupus erythematosus and association with Neuropsychopharmacology 12: 447–458. antiphospholipid antibodies. Journal of Rheumatology 33: 1873–1877. Kayser MS and Dalmau J (2011) The emerging link between autoimmune Harley JB (2002) The genetic etiology of systemic lupus erythematosus: disorders and neuropsychiatric disease. Journal of Neuropsychiatry a short dispatch from the combat zone. Genes and Immunity 3, S1–4. and Clinical Neurosciences 23: 90–97. Harris MG and Fabry Z (2012) Initiation and regulation of CNS auto- Kayser MS, Kohler CG and Dalmau J (2010) Psychiatric manifestations immunity: balancing immune surveillance and inflammation in the of paraneoplastic disorders. American Journal of Psychiatry 167: CNS. Neuroscience and Medicine 3: 203–224. 1039–1050. Hashimoto K, Sawa A and Iyo M (2007) Increased levels of glutamate Kim YK, Jung HG, Myint AM, et al. (2007) Imbalance between pro- in brains from patients with mood disorders. Biological Psychiatry inflammatory and anti-inflammatory cytokines in bipolar disorder. 62:1310–1316. Journal of Affective Disorders 104: 91–95. Hermosillo-Romo D and Brey RL (2002) Diagnosis and management of Konradi C, Sillivan SE and Clay HB (2012) Mitochondria, oligodendro- patients with neuropsychiatric systemic lupus erythematosus (NPSLE). cytes and inflammation in bipolar disorder: evidence from transcrip- Best Practice and Research. Clinical Rheumatology 16: 229–244. tome studies points to intriguing parallels with multiple sclerosis. Hillegers MH, Reichart CG, Wals M, et al. (2007) Signs of a higher preva- Neurobiology of Disease 45: 37–47. lence of autoimmune thyroiditis in female offspring of bipolar par- Knight JG, Menkes DB, Highton J, et al. (2007) Rationale for a trial ents. European Neuropsychopharmacology 17: 394–399. of immunosuppressive therapy in acute schizophrenia. Molecular Hu S, Peterson PK and Chao CC (1997) Cytokine-mediated neuronal Psychiatry 12: 424–431. apoptosis. Neurochemistry International 30: 427–431. Krishnadas R and Cavanagh J (2012) Depression: an inflammatory illness? Huang EJ and Reichardt LF (2001) Neurotrophins: roles in neuronal devel- Journal of Neurology, Neurosurgery and Psychiatry 83: 495–502. opment and function. Annual Review of Neuroscience 24: 677–736. Kupka RW, Nolen WA, Post RM, et al. (2002) High rate of autoimmune Hughes GRV (1998) Is it lupus? The St. Thomas’ Hospital “alternative” thyroiditis in bipolar disorder: lack of association with lithium expo- criteria. Clinical and Experimental Rheumatology 16: 250–252. sure. Biological Psychiatry 51: 305–311. Iancu I, Sverdlik A, Dannon PN, et al. (1997) Bipolar disorder associ- La Cava A (2009) Natural Tregs and autoimmunity. Frontiers in Bioscience ated with interferon-alpha treatment. Postgraduate Medical Journal 14: 333. 73: 834. La Cava A and Matarese G. (2004) The weight of leptin in immunity. International Schizophrenia Consortium, Purcell SM, Wray NR, et al. Nature Reviews Immunology 4: 371–379. (2009) Common polygenic variation contributes to risk of schizo- Lampron A, ElAli A and Rivest S (2013) Innate immunity in the CNS: phrenia and bipolar disorder. Nature 460: 748–752. redefining the relationship between the CNS and its environment. Issa G, Wilson C, Terry AV, et al. (2010) An inverse relationship between Neuron 78: 214–232. cortisol and BDNF levels in schizophrenia: data from human post- Langan C and McDonald C. (2009) Neurobiological trait abnormalities in mortem and animal studies. Neurobiology of Disease 39: 327–333. bipolar disorder. Molecular Psychiatry 14: 833–846. Johansson V, Nybom R, Wetterberg L, et al. (2012) Microscopic particles Lin PY (2009) State-dependent decrease in levels of brain-derived neuro- in two fractions of fresh cerebrospinal fluid in twins with schizophre- trophic factor in bipolar disorder: a meta-analytic study. Neuroscience nia or bipolar disorder and in healthy controls. PLoS One, 7: e45994. Letters 466: 139–143.

Australian & New Zealand Journal of Psychiatry, 47(12) 1150 ANZJP Articles

Liu CY, Tseng MC and Lin PH (2011a) Encephalopathy associated with resistance and relevance to depression. Advances in Experimental autoimmune thyroid disease (Hashimoto’s thyroiditis) presenting Medicine and Biology 461: 107–116. as depression: a case report. General Hospital Psychiatry 33:, Miller CL, Llenos IC, Dulay JR, et al. (2006) Upregulation of the initiating 641.e647–e649. step of the kynurenine pathway in postmortem anterior cingulate cor- Liu W, Tang Y and Feng J (2011b) Cross talk between activation of micro- tex from individuals with schizophrenia and bipolar disorder. Brain glia and astrocytes in pathological conditions in the central nervous Research 1073: 25–37. system. Life Sciences 89: 141–146. Mocellin R, Walterfang M and Velakoulis D (2007) Hashimotos encepha- López-Armada MJ, Riveiro-Naveira RR, Vaamonde-García C, et al. lopathy: epidemiology, pathogenesis and management. CNS Drugs (2013) Mitochondrial dysfunction and the inflammatory response. 21: 799–811. Mitochondrion 13: 106–118. Monje ML, Toda H and Palmer TD (2003) Inflammatory blockade restores Losif RE, Ekdahl CT, Ahlenius H, et al. (2006) Tumor necrosis factor adult hippocampal neurogenesis. Science 302: 1760–1765. receptor 1 is a negative regulator of progenitor proliferation in adult Monov S and Monova D (2008) Classification criteria for neuropsy- hippocampal neurogenesis. Journal of Neuroscience 26: 9703–9712. chiatric systemic lupus erythematosus: do they need a discussion? Luo XG and Chen SD (2012) The changing phenotype of microglia from Hippokratia 12: 103–107. homeostasis to disease. Translational Neurodegeneration 1: 1–13. Moscavitch SD, Szyper-Kravitz M and Shoenfeld Y (2009) Autoimmune Maat P, Graaff E, Beveren NM, et al. (2012) Psychiatric phenomena as ini- pathology accounts for common manifestations in a wide range of tial manifestation of encephalitis by anti-NMDA receptor antibodies. neuro-psychiatric disorders: the olfactory and immune system inter- Acta Neuropsychiatrica doi:10.1111/acn.12013 (Epub ahead of print). relationship. Clinical Immunology 130: 235–243. McIntosh AM, Maniega SM, Lymer GKS, et al. (2008) White matter trac- Mosmann TR and Sad S (1996) The expanding universe of T-cell subsets: tography in bipolar disorder and schizophrenia. Biological Psychiatry Th1, Th2 and more. Immunology Today 17: 138–146. 64: 1088–1092. Mössner R, Heils A, Stöber G, et al. (1998) Enhancement of serotonin McKernan DP, Dennison U, Gaszner G, et al. (2011) Enhanced peripheral transporter function by tumor necrosis factor alpha but not by inter- toll-like receptor responses in psychosis: further evidence of a pro- leukin-6. Neurochemistry International 33: 251–254. inflammatory phenotype. Translational Psychiatry 1: e36. Munkholm K, Vinberg M and Vedel Kessing L (2013) Cytokines in Maes M, Delange J, Ranjan R, et al. (1997) Acute phase proteins in schiz- bipolar disorder: a systematic review and meta-analysis. Journal of ophrenia, mania and major depression: modulation by psychotropic Affective Disorders 144: 16–27. drugs. Psychiatry Research 66: 1–11. Muscal E and Brey RL (2010) Neurologic manifestations of systemic lupus Maes M, Fišar Z, Medina M, et al. (2012a) New drug targets in depres- erythematosus in children and adults. Neurologic Clinics 28, 61–73. sion: inflammatory, cell-mediated immune, oxidative and nitrosative Mussig K, Bartels M, Gallwitz B, et al. (2005) Hashimoto’s encephalopa- stress, mitochondrial, antioxidant, and neuroprogressive pathways. thy presenting with bipolar affective disorder. Bipolar Disorders 7: And new drug candidates – Nrf2 activators and GSK-3 inhibitors. 292–297. Inflammopharmacology 20: 127–150. Najjar S, Pearlman DM, Alper K, et al. (2013) Neuroinflammation and Maes M, Meltzer HY and Bosmans E (2007) Immune-inflammatory psychiatric illness. Journal of Neuroinflammation 10: 43. markers in schizophrenia: comparison to normal controls and effects Neuwelt CM and Young RG (2009) Managing neuropsychiatric lupus: of clozapine. Acta Psychiatrica Scandinavica 89: 346–351. top 10 clinical pearls. Clinical judgment and experience must pre- Maes M, Mihaylova I, Kubera M, et al. (2011) IgM-mediated autoim- vail. Available at: www.musculoskeletalnetwork.com/display/arti- mune responses directed against multiple neoepitopes in depression: cle/1145622/1396901 (consulted January 2013). new pathways that underpin the inflammatory and neuroprogressive Ng PC, Li K, Wong RP, et al. (2003) Proinflammatory and anti-inflamma- pathophysiology, Journal of Affective Disorders 135: 414–418. tory cytokine responses in preterm infants with systemic infections. Maes M, Ringel K, Kubera M, et al. (2012b) Increased autoimmune Archives of Disease in Childhood. Fetal and Neonatal Edition 88: activity against 5-HT: a key component of depression that is asso- F209–213. ciated with inflammation and activation of cell-mediated immunity, Nguyen MD, Julien JP and Rivest S (2002) Innate immunity: the miss- and with severity and staging of depression. Journal of Affective ing link in neuroprotection and neurodegeneration? Nature Reviews Disorders 136: 386–392. Neuroscience 3: 216–227. Mahon K, Burdick KE and Szeszko PR (2010) A role for white mat- O’Brien SM, Scully P, Scott LV, et al. (2006) Cytokine profiles in bipolar ter abnormalities in the pathophysiology of bipolar disorder. affective disorder: focus on acutely ill patients. Journal of Affective Neuroscience and Biobehavioral Reviews 34: 533–554. Disorders 90: 263–267. Mak A, Ho RCM and Lau CS (2009) Clinical implications of neuropsy- Okamoto H, Kobayashi A and Yamanaka H (2010) Cytokines and chiatric systemic lupus erythematosus. Advances in Psychiatric chemokines in neuropsychiatric syndromes of systemic lupus ery- Treatment 15: 451–458. thematosus. Journal of Biomedicine and Biotechnology 2010, Malek-Ahmadi P (2001) Mood disorders associated with interferon 268436. treatment: theoretical and practical considerations. Annals of Omdal R, Brokstad K, Waterloo K, et al. (2005) Neuropsychiatric distur- Pharmacotherapy 35: 489–495. bances in SLE are associated with antibodies against NMDA recep- Manji HK, Moore GJ, Rajkowska G, et al. (2000) Neuroplasticity and cel- tors. European Journal of Neurology 12: 392–398. lular resilience in mood disorders. Molecular Psychiatry 5: 578–593. Ortiz-Dominguez A, Hernandez ME, Berlanga C, et al. (2007) Immune Marshak-Rothstein A (2006) Toll-like receptors in systemic autoimmune variations in bipolar disorder: phasic differences. Bipolar Disorders disease. Nature Reviews Immunology 6: 823–835. 9: 596–602. Meinl E, Krumbholz M and Hohlfeld R (2006) B lineage cells in the O’Shea JJ, Ma A and Lipsky P (2002) Cytokines and autoimmunity. inflammatory central nervous system environment: migration, main- Nature Reviews Immunology 2: 37–45. tenance, local antibody production, and therapeutic modulation. Pacheco R, Gallart T, Lluis C, et al. (2007) Role of glutamate on T-cell Annals of Neurology 59: 880–892. mediated immunity. Journal of Neuroimmunology 185: 9–19. Miller AH, Maletic V and Raison CL (2009) Inflammation and its discon- Padmos RC, Bekris L, Knijff EM, et al. (2004) A high prevalence of organ- tents: the role of cytokines in the pathophysiology of major depres- specific autoimmunity in patients with bipolar disorder. Biological sion. Biological Psychiatry 65: 732–741. Psychiatry. 56: 476–482. Miller AH, Pariante CM and Pearce BD (1999) Effects of cytokines on Padmos RC, Hillegers MH, Knijff EM, et al. (2008) A discriminating glucocorticoid receptor expression and function. Glucocorticoid messenger RNA signature for bipolar disorder formed by an aberrant

Australian & New Zealand Journal of Psychiatry, 47(12) Rege and Hodgkinson 1151

expression of inflammatory genes in monocytes. Archives of General Stockinger B and Veldhoen M (2007) Differentiation and function of Th17 Psychiatry 65: 395–407. T cells. Current Opinion in Immunology 19: 281–286. Padmos RC, Van Baal GCM, Vonk R, et al. (2009) Genetic and environ- Stojanovich L and Marisavljevich D (2008) Stress as a trigger of autoim- mental influences on pro-inflammatory monocytes in bipolar disor- mune disease. Autoimmunity Reviews 7: 209–213. der: a twin study. Archives of General Psychiatry 66: 957. Stout SC and Nemeroff CB (1994) Stress and psychiatric disorders. Petri M, Naqibuddin M, Carson KA, et al. (2008) Brain magnetic reso- Seminars in Neuroscience 6: 271–280. nance imaging in newly diagnosed systemic lupus erythematosus. Tedla Y, Shibre T, Ali O, et al. (2011) Serum antibodies to Toxoplasma Journal of Rheumatology 35: 2348–2354. gondii and Herpesvidae family viruses in individuals with schizo- Plotnikoff NP (2007) Cytokines: stress and immunity. Boca Raton, FL: phrenia and bipolar disorder: a case-control study. Ethiopian Medical CRC Press. Journal 49: 211. Popescu A and Kao AH (2011) Neuropsychiatric systemic lupus erythe- Thomas AJ, Davis S, Ferrier IN, et al. (2004) Elevation of cell adhesion matosus. Current Neuropharmacology 9: 449–457. molecule immunoreactivity in the anterior cingulate cortex in bipolar Rao JS, Harry GJ, Rapoport SI, et al. (2010) Increased excitotoxicity and disorder. Biological Psychiatry 55: 652–655. neuroinflammatory markers in postmortem frontal cortex from bipo- Tyring S, Gottlieb A, Papp K, et al. (2006) Etanercept and clinical out- lar disorder patients. Molecular Psychiatry 15: 384–392. comes, fatigue, and depression in psoriasis: double-blind placebo- Ransohoff RM and Brown MA (2012) Innate immunity in the central controlled randomised phase III trial. Lancet 367: 29–35. nervous system. Journal of Clinical Investigation 122: 1164–1171. Valles SL, Blanco AM, Pascual M, et al. (2004) Chronic ethanol treatment Renault PF, Hoofnagle JH, Park Y, et al. (1987) Psychiatric complications enhances inflammatory mediators and cell death in the brain and in of long-term interferon alfa therapy. Archives of Internal Medicine astrocytes. Brain Pathology 14: 365–371. 147: 1577–1580. Viviani B, Bartesaghi S, Gardoni F, et al. (2003) Interleukin-1β enhances Rohleder N, Wolf JM, Kirschbaum C, et al. (2009) Effects of cortisol NMDA receptor-mediated intracellular calcium increase through activa- on emotional but not on neutral memory are correlated with periph- tion of the Src family of kinases. Journal of Neuroscience 23: 8692–8700. eral glucocorticoid sensitivity of inflammatory cytokine production. Vonk R, van der Schot AC, Kahn RS, et al. (2007) Is autoimmune thyroidi- International Journal of Psychophysiology 72: 74–80. tis part of the genetic vulnerability (or an endophenotype) for bipolar Rosenfeld MR and Dalmau J (2011) Anti-NMDA-receptor encephalitis disorder? Biological Psychiatry 62: 135–140. and other synaptic autoimmune disorders. Current Treatment Options Wadee AA, Kuschke RH, Wood LA, et al. (2002) Serological obser- in Neurology 13: 324–332. vations in patients suffering from acute manic episodes. Human Rossi B, Angiari S, Zenaro E, et al. (2011) Vascular inflammation in central Psychopharmacology: Clinical and Experimental 17: 175–179. nervous system diseases: adhesion receptors controlling leukocyte- Waite JC and Skokos D (2012) Th17 response and inflammatory autoim- endothelial interactions. Journal of Leukocyte Biology 89: 539–556. mune diseases. International Journal of Inflammation 2012, 819467. Santer DM, Yoshio T, Minota S, et al. (2009) Potent induction of IFN-alpha Wallace DJ and Hahn BH (2006) Dubois’ lupus erythematosus. and chemokines by autoantibodies in the cerebrospinal fluid of patients Philadelphia, PA: Lippincott Williams and Wilkins. with neuropsychiatric lupus. Journal of Immunology 182: 1192–1201. Webster MJ, O’Grady J, Kleinman JE, et al. (2005) Glial fibrillary acidic Schroeter ML, Sacher J, Steiner J, et al. (2013) Serum S100B represents protein mRNA levels in the cingulate cortex of individuals with depres- a new biomarker for mood disorders. Current Drug Targets (Epub sion, bipolar disorder and schizophrenia. Neuroscience 133: 453–61. ahead of print). Wright MT (2010) Neuropsychiatric illness in systemic lupus erythema- Segerstrom SC and Miller GE (2004) Psychological stress and the tosus: insights from a patient with erotomania and Geschwind’s syn- human immune system: a meta-analytic study of 30 years of inquiry. drome. American Journal of Psychiatry 167: 502–507. Psychological Bulletin 130: 601–630. Yeh HM and Hu SY (2007) Mania as an initial feature of systemic lupus Shalev H, Serlin Y and Friedman A (2009) Breaching the blood–brain bar- erythematosus: a case report. Journal of Internal Medicine of Taiwan rier as a gate to psychiatric disorder. Cardiovascular Psychiatry and 18: 283–286. Neurology 2009, 278531. Yu HH, Lee JH, Wang LC, et al. (2006) Neuropsychiatric manifestations Sidhom O, Laadhar L, Zitouni M, et al. (2012) Spectrum of autoantibod- in pediatric systemic lupus erythematosus: a 20-year study. Lupus 15: ies in Tunisian psychiatric inpatients. Immunological Investigations 651–657. 41: 538–549. Zanetti MV, Jackowski MP, Versace A, et al. (2009) State-dependent micro- Smith TJ (2010) Insulin-like growth factor-I regulation of immune structural white matter changes in bipolar I depression. European function: a potential therapeutic target in autoimmune diseases? Archives of Psychiatry and Clinical Neuroscience 259: 316–328. Pharmacological Reviews 62: 199–236. Zhang B, Angelidou A, Alysandratos KD, et al. (2010) Mitochondrial Soczynska JK, Kennedy SH, Goldstein BI, et al. (2009) The effect of DNA and anti-mitochondrial antibodies in serum of autistic children. tumor necrosis factor antagonists on mood and mental health-asso- J Neuroinflammation 7: 80. ciated quality of life: novel hypothesis-driven treatments for bipolar Zhu CB, Carneiro AM, Dostmann WR, et al. (2005) p38 MAPK activa- depression? Neurotoxicology 30: 497–521. tion elevates serotonin transport activity via a trafficking-independ- Soderlund J, Olsson SK, Samuelsson M, et al. (2011) Elevation of cer- ent, protein phosphatase 2A-dependent process. Journal of Biological ebrospinal fluid interleukin-1 beta in bipolar disorder. Journal of Chemistry 280: 15649–15658. Psychiatry and Neuroscience 36: 114–118. Zhu J and Paul WE (2008) CD4 T cells: fates, functions, and faults. Blood Spivak B, Radwan M, Bartur P, et al. (1996) Antinuclear autoantibodies 112: 1557–1569. in relation to bipolar affective disorder and lithium therapy. European Zotova E, Nicoll JA, Kalaria R, et al. (2010) Inflammation in Alzheimer’s Psychiatry 11: 50–52. disease: relevance to pathogenesis and therapy. Alzheimers Research Squassina A, Costa M, Congiu D, et al. (2013) Insulin-like growth fac- and Therapy 2: 1. tor 1 (IGF-1) expression is up-regulated in lymphoblastoid cell lines Zou J, Wang YX, Dou FF, et al. (2010) Glutamine synthetase down-regu- of lithium responsive bipolar disorder patients. Pharmacological lation reduces astrocyte protection against glutamate excitotoxicity to Research 73C: 1–7. neurons. Neurochemistry International 56: 577–584.

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