Herpesvirus may lead to bipolar, depression

An international team of scientists led by Bhupesh Prusty — from the
Department of Microbiology at the University of Würzburg in Germany —
discovered that in the brains of people who lived with bipolar and major
depression, a class of neurons called Purkinje cells was infected with
the herpesvirus HHV-6A.
Purkinje neurons are inhibitory brain cells located in the human cerebellum, which is
the brain area responsible for controlling movement, muscles, balance,
and posture.
However, some research has also tied this brain region to language, cognition, and mood.

Active HHV-6 Infection of Cerebellar Purkinje Cells in Mood Disorders Frontiers in microbiology

Reduced maternal levels of common viruses during pregnancy predict offspring psychosis: potential role of enhanced maternal immune activity? - PubMed - NCBI

Viral infections during the prenatal or early childhood periods are one of the environmental factors which might play an etiological role in psychoses. Several studies report higher antibody levels against viruses during pregnancy in blood of mothers of offspring with psychotic disorders, but the presence of such viruses has never been demonstrated. The goal of this study was to investigate the potential association between viral infections during pregnancy and progeny with psychotic disorders and, for this purpose, we performed a nested case-control study involving pregnant mothers of offspring with schizophrenia or bipolar disorder with psychotic features (cases, N=43) and pregnant women with healthy offspring (controls, N=95). Since several potential viral candidates have been suggested in prior work, a broad-spectrum virus detection system was necessary. A metagenomic analysis performed with the virus discovery method VIDISCA-454 revealed only common blood-associated viruses in all cohorts. However, a significantly lower viral prevalence was detected in the group of cases and in the sub-population of pregnant mothers of offspring with schizophrenia (p<0.05). Consistent with the existing inverse correlation between the level of these viruses and the immunocompetence of an individual, we hypothesized the presence of a higher immune activity during pregnancy in mothers whose offspring later develop a psychotic disorder as compared to controls. Combining our results with previously available literature data on antibody levels during the gestation period suggests that a more prominent maternal immune activity can be considered a risk factor for developing psychosis.



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Yeast infection linked to mental illness: Schizophrenia and bipolar disorder

In a study prompted in part by suggestions from people with mental illness, Johns Hopkins researchers found that a history of Candida yeast infections was more common in a group of men with schizophrenia or bipolar disorder than in those without these disorders, and that women with schizophrenia or bipolar disorder who tested positive for Candida performed worse on a standard memory test than women with schizophrenia or bipolar disorder who had no evidence of past infection."

A meta-analysis of blood cytokine network alterations in psychiatric patients: comparisons between schizophrenia, bipolar disorder and depression : Molecular Psychiatry

 "Schizophrenia, bipolar disorder and major depressive disorder (MDD) have all been associated with aberrant blood cytokine levels; however, neither the pattern of cytokine alterations nor the impact of clinical status have been compared across disorders. We performed a meta-analysis of blood cytokines in acutely and chronically ill patients with these major psychiatric disorders. Articles were identified by searching the PubMed, PsycInfo and Web of Science, and the reference lists of these studies. Sixty-eight studies met the inclusion criteria (40 schizophrenia, 10 bipolar disorder and 18 MDD) for acutely ill patients. Forty-six studies met the inclusion criteria (18 schizophrenia, 16 bipolar disorder and 12 MDD) for chronically ill patients. Levels of two cytokines (interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α)), one soluble cytokine receptor (sIL-2R), and one cytokine receptor antagonist (IL-1RA) were significantly increased in acutely ill patients with schizophrenia, bipolar mania and MDD compared with controls (P<0.01). Following treatment of the acute illness, IL-6 levels significantly decreased in both schizophrenia and MDD (P<0.01); sIL-2R levels increased in schizophrenia; and IL-1RA levels in bipolar mania decreased. In chronically ill patients, the levels of IL-6 were significantly increased in schizophrenia, euthymic (but not depressed) bipolar disorder and MDD compared with controls (P<0.01). The levels of IL-1β and sIL-2R were significantly increased in both chronic schizophrenia and euthymic bipolar disorder. Overall, there were similarities in the pattern of cytokine alterations in schizophrenia, bipolar disorder and MDD during acute and chronic phases of illness, raising the possibility of common underlying pathways for immune dysfunction. Effects of treatment on cytokines were more robust for schizophrenia and MDD, but were more frequently studied than for acute mania. These findings have important implications for our understanding of the pathophysiology and treatment of major psychiatric disorders."



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Cytomegalovirus Antibody Elevation in Bipolar Disorder: Relation to Elevated Mood States. - PubMed - NCBI

The neurobiology of mood states is complicated by exposure to everyday stressors (e.g., psychosocial, ubiquitous environmental infections like CMV), each fluctuating between latency and reactivation. CMV reactivation induces proinflammatory cytokines (e.g., TNF-alpha) associated with induction of neurotoxic metabolites and the presence of mood states in bipolar disorder (BD). Whether CMV reactivation is associated with bipolar diagnoses (trait) or specific mood states is unclear. We investigated 139 BD type I and 99 healthy controls to determine if concentrations of IgG antibodies to Herpesviridae (e.g., CMV, HSV-1, and HSV-2) were associated with BD-I diagnosis and specific mood states. We found higher CMV antibody concentration in BD-I than in healthy controls (T234 = 3.1, P uncorr = 0.002; P corr = 0.006) but no difference in HSV-1 (P > 0.10) or HSV-2 (P > 0.10). Compared to euthymic BD-I volunteers, CMV IgG was higher in BD-I volunteers with elevated moods (P < 0.03) but not different in depressed moods (P > 0.10). While relationships presented between BD-I diagnosis, mood states, and CMV antibodies are encouraging, they are limited by the study's cross sectional nature. Nevertheless, further testing is warranted to replicate findings and determine whether reactivation of CMV infection exacerbates elevated mood states in BD-I

Immune alterations in acute bipolar depression. - PubMed - NCBI

OBJECTIVE:

Immunologic abnormalities have been found in bipolar disorder and acute mania.
However, there have been fewer studies of patients with acute bipolar
depression.

METHOD:

Blood samples were obtained from individuals with acute bipolar depression,
acute mania, and controls. These samples were evaluated for antibodies
to human herpesviruses, gliadin, Toxoplasma gondii, and endogenous
retroviruses as well as for C-reactive protein (CRP) and pentraxin-3
using immunoassay methods. Linear regression models were used to compare
the levels of the markers controlling for demographic and clinical
variables. A subset of the bipolar depressed group was evaluated at a
6-month follow-up.

RESULTS:

The sample consisted of 82 individuals with acute bipolar depression, 147
with acute mania, and 280 controls. The levels of CRP and IgG antibodies
to an endogenous retrovirus, Mason-Pfizer monkey virus (MPMV), were
significantly elevated in the bipolar depressed group. Levels of
pentraxin-3 were reduced in both psychiatric groups. An evaluation of 32
individuals 6 months after hospitalization for bipolar depression
showed a significant decrease in the levels of MPMV antibodies, but not a
change in the other markers.

CONCLUSION:

Individuals with acute bipolar depression show immune alterations. Some of the
alterations are similar to those found in acute mania.

Could owning a cat raise the risk of mental illness? - Medical News Today

They are cute, fluffy and have that wide-eyed glare that few of us can resist; it is no wonder more than 95 million of us own a cat. But there may be a darker side to our four-legged friends. New research claims the animals could increase our risk of mental illnesses, including schizophrenia and bipolar disorder.
Two studies published in the journals Schizophrenia Research and Acta Psychiatrica Scandinavica attribute this association to Toxoplasma gondii - a parasite found in the intestines of cats. Humans can become infected with the parasite by accidentally swallowing it after coming into contact with the animal's feces.

T. gondii is the cause of a disease known as toxoplasmosis. According to the Centers for Disease Control and Prevention (CDC), more than 60 million people in the US are infected with the parasite, though the majority of people are not aware of it.

Toxoplasmosis and Polygenic Disease Susceptibility Genes: Extensive Toxoplasma gondii Host/Pathogen Interactome Enrichment in Nine Psychiatric or Neurological Disorders

Infection and Inflammation in Schizophrenia and Bipolar Disorder: A Genome Wide Study for Interactions with Genetic Variation.

Inflammation and maternal or fetal infections have been suggested as
risk factors for schizophrenia (SZ) and bipolar disorder (BP). It is
likely that such environmental effects are contingent on genetic
background. Here, in a genome-wide approach, we test the hypothesis that
such exposures increase the risk for SZ and BP and that the increase is
dependent on genetic variants. We use genome-wide genotype data, plasma
IgG antibody measurements against Toxoplasma gondii, Herpes simplex
virus type 1, Cytomegalovirus, Human Herpes Virus 6 and the food antigen
gliadin as well as measurements of C-reactive protein (CRP), a
peripheral marker of inflammation. The subjects are SZ cases, BP cases,
parents of cases and screened controls. We look for higher levels of our
immunity/infection variables and interactions between them and common
genetic variation genome-wide. We find many of the antibody measurements
higher in both disorders. While individual tests do not withstand
correction for multiple comparisons, the number of nominally significant
tests and the comparisons showing the expected direction are in
significant excess (permutation p=0.019 and 0.004 respectively). We also
find CRP levels highly elevated in SZ, BP and the mothers of BP cases,
in agreement with existing literature, but possibly confounded by our
inability to correct for smoking or body mass index. In our genome-wide
interaction analysis no signal reached genome-wide significance, yet
many plausible candidate genes emerged. In a hypothesis driven test, we
found multiple interactions among SZ-associated SNPs in the HLA region
on chromosome 6 and replicated an interaction between CMV infection and
genotypes near the CTNNA3 gene reported by a recent GWAS. Our results
support that inflammatory processes and infection may modify the risk
for psychosis and suggest that the genotype at SZ-associated HLA loci
modifies the effect of these variables on the risk to develop SZ.

Treatment with Anti-Toxoplasmic Activity (TATA) for Toxoplasma positive patients with bipolar disorders or schizophrenia: a cross-sectional study - Journal of Psychiatric Research

The association between Toxoplasma gondii seropositivity and respectively Bipolar Disorder (BD) and Schizophrenia/Schizoaffective disorder (SZ) is one of the most studied link between one pathogen and psychiatric disorders. The aim of the present study was thus to retrospectively determine if the administration of an antipsychotic and/or a mood stabilizer having known in vitro Anti-Toxoplasmic Activity (TATA+) was associated with a better clinical outcome in a population of 152 BD or 114 SZ patients and seropositive for T. gondii infection compared to patients receiving a treatment without anti-toxoplasmic activity (TATA-).

Methods

This multicenter study was conducted in an academic public hospital during a 3-years period between 2009 and 2011. All consecutive inpatients and outpatients with SZ or BD diagnosis with a stable treatment for more than 4 weeks were recruited. socio-demographic and clinical characteristics measured with validated scales as well as a serological status for toxoplasmic infection were included. Treatments were classified according to their in vitro antitoxoplasmic activity. A multivariate model was used to determine the clinical characteristics that were significantly different between patients receiving a treatment with no antitoxoplasmic activity compared to others.

Results

BD patients with positive serum antibodies against T. gondii presented more lifetime depressive episodes (p=0.048) after adjustment for age, sex and sociodemographic characteristics when treated by drug having no anti-toxo activity, compared to patients having received drugs with anti-toxo activity. A significant difference was not found in BD toxonegative patients and in SZ toxopositive or toxonegative patients.

Conclusions

It seems to be of importance to consider prescribing a drug with a clear anti-toxoplasmic activity (TATA+) for BD patients seropositive to T. gondii, in particular valproate that was found as the mood stabilizer with the highest antitoxoplasmic activity. Prospective randomized controlled trials are warranted to confirm this preliminary data.

Neuroprotective kynurenine metabolite indices are abnormally reduced and positively associated with hippocampal and amygdalar volume in bipolar disorder.

Inflammation-related changes in the concentrations of kynurenine-pathway
metabolites occur in depression secondary to medical conditions but
have not been well characterized in primary bipolar disorder (BD), with
contradictory results potentially attributable to the presence or
absence of psychosis and/or medication effects. In contrast, reductions
in hippocampal and amygdalar volume that theoretically reflect dendritic
atrophy occurring in the context of a neurotoxic process are commonly
reported in unmedicated BD patients. Here we tested whether the
concentrations of putatively neuroprotective (kynurenic acid, KynA) and neurotoxic (3-hydroxy-kynurenine, 3HK and quinolinic acid,
QA) kynurenine-pathway metabolites were altered in primary BD and
whether these metabolites were associated with hippocampal and amygdalar
volume. Twenty-five moderately-to-severely depressed unmedicated
subjects and 38 moderately-to-severely depressed medicated subjects who
met DSM-IV-TR criteria for BD, as well as 48 healthy controls (HCs)
completed a structural MRI scan and provided a blood sample for
kynurenine metabolite analysis, performed using high performance liquid
chromatography with tandem mass spectrometry. Gray matter volumes were
measured with the automated segmentation software, FreeSurfer. A
putative neuroprotective index, KynA/QA, was significantly lower in the
BD subjects relative to the HCs, a finding that was unrelated to current
treatment with medication or a prior history of psychosis. Further,
another putative neuroprotective index, KynA/3HK was positively
associated with hippocampal volume in the BD group after controlling for
age, sex, body mass index (BMI), and intracranial volume (ICV). Kyn/3HK
was significantly associated with total amygdalar volume in the BD
group, but after controlling for age, sex, BMI, but not ICV, this
association was reduced to a trend. In addition, Kyn/3HK was positively
associated with amygdalar volume in the HCs although the association was
no longer significant after accounting for the effects of age, sex, and
BMI. The results raise the possibility that BD-associated abnormalities
in kynurenine metabolism may impact the structure of the hippocampus
and amygdala, highlighting a pathway through which inflammation may
exert neuropathological effects in the context of depression.

Antibodies to Toxoplasma gondii in individuals with mania.

Increased rates of infection with Toxoplasma gondii have been found in individuals with schizophrenia as compared to control groups but this issue has not been studied in mania.

METHODS:

We measured immunoglobulin G (IgG) and IgM class antibodies to T. gondii in 57 individuals with mania who were assessed at up to three time-points. We also measured these antibodies in 743 individuals in other psychiatric groups and in 314 non-psychiatric controls. T. gondii antibody levels were compared among groups by multivariate analyses. IgG class and IgM class antibodies to cytomegalovirus were also measured in the same samples. T. gondii antibody levels were also compared over time in the mania group.

RESULTS:

The mania group had a significantly elevated level of IgM antibodies to T. gondii as compared to the control individuals without a psychiatric diagnosis [odds ratio (OR) = 2.33, p < 0.04 at hospital admission  and OR = 2.32, p < 0.02 at study entry during the hospital stay]. Elevated IgM class antibodies to T. gondii were not found in individuals with the other psychiatric diagnoses. We also did not find an increased level of IgG class antibodies to T. gondii or IgG or IgM class antibodies to CMV in the individuals with mania. Within the mania group, there was a significant difference between the prevalences of increased levels of T. gondii IgM at the baseline and the follow-up time-point (t = 2.97, p < 0.003).

CONCLUSIONS:

Infection with T. gondii may confer risk for mania.

Borna disease virus (BDV) infection in psychiatric patients and healthy controls in Iran.

BACKGROUND:

Borna disease virus (BDV) is an evolutionary old RNA virus, which infects brain and blood cells of
humans, their primate ancestors, and other mammals. Human infection has been correlated to mood disorders and schizophrenia, but the impact of BDV on mental-health still remains controversial due to poor methodological and cross-national comparability.

METHOD:

This
first report from the Middle East aimed to determine BDV infection
prevalence in Iranian acute psychiatric disorder patients and healthy
controls through circulating immune complexes (CIC), antibodies (Ab) and
antigen (pAg) in blood plasma using a standardized triple enzyme immune
assay (EIA). Samples of 314 subjects (114 psychiatric cases, 69 blood
donors, and 131 healthy controls) were assayed and data analyzed
quantitatively and qualitatively.

RESULTS:

CICs revealed a BDV prevalence of one third (29.5%) in healthy Iranian controls (27.5%
controls; 33.3% blood donors). In psychiatric patients CIC prevalence
was higher than in controls (40.4%) and significantly correlating with
bipolar patients exhibiting overt clinical symptoms (p = 0.005, OR =
1.65). CIC values were significantly elevated in bipolar (p = 0.001) and
major depressive disorder (p = 0.029) patients as compared to controls,
and in females compared to males (p = 0.031).

CONCLUSION:

This study supports a similarly high prevalence of subclinical human BDV
infections in Iran as reported for central Europe, and provides again an
indication for the correlation of BDV infection and mood disorders.
Further studies should address the morbidity risk for healthy carriers
and those with elevated CIC levels, along with gender disparities.

An observational study of inflammation in the central nervous system in patients with bipolar disorder.

OBJECTIVES:

The potential influence of infections andimmunological changes on the aetiology and pathogenesis of bipolar disorder (BD) has been discussed. Our aim was to detect intrathecal specific antibody synthesis against the neurotropic infectious agents that have previously been linked to BD.

METHODS:

Paired cerebrospinal fluid (CSF) and serum samples from 40 patients with BD
were analysed using the enzyme-linked immunosorbent assay to detect the
concentration of antibodies against the following neurotropic infectious
pathogens: Toxoplasma gondii (T. gondii), herpes simplex virus (HSV)
types 1 and 2, cytomegalovirus (CMV), and Epstein-Barr virus (EBV). The
specific antibody index (AI) was calculated, and an AI > 1.4 was
considered to be evidence of intrathecal specific antibody synthesis.
Twenty-six patients with pseudotumour cerebri served as controls.

RESULTS:

Eight out of 40 patients with BD displayed specific intrathecal antibody synthesis against at least one of the tested neurotropic agents compared to only one patient in the control group (p = 0.061, not significant) . Of these eight patients with BD, no significant prevalence of any particular neurotropic pathogen was evident. Five out of 40 patients with BD showed oligoclonal bands in the CSF, suggestive of a chronic immune reaction in the central nervous system (CNS).

CONCLUSIONS:

We found evidence for increased production of antibody in the CSF of individuals with BD. However, the trend for polyspecific intrathecal antibody synthesis, as well as the presence of oligoclonal bands, might indicate activation of the intrathecal humoral immune system in a subgroup of patients with BD, as it is known to be associated with autoimmune disorders of the CNS.

Cytomegalovirus seropositivity and serointensity are associated with hippocampal volume and verbal memory in schizophrenia and bipolar disorder.

Cytomegalovirus (CMV) is a member of the herpesviridae family that
has a limbic and temporal gray matter tropism. It is usually latent in
humans but has been associated with schizophrenia, bipolar disorder and
cognitive deficits in some populations. Hippocampal decreased volume and
dysfunction play a critical role in these cognitive deficits. We
hypothesized that CMV seropositivity and serointensity would be
associated with hippocampal volume and cognitive functioning in patients
with schizophrenia or bipolar disorder.

METHODS:

102 healthy controls, 118 patients with bipolar disorder and 69 patients
with schizophrenia performed the California Verbal Learning Test (CVLT)
and had blood samples drawn to assess CMV IgG levels. A subgroup of 52
healthy controls, 31 patients with bipolar disorder and 27 patients with
schizophrenia underwent T1 MRI for hippocampal volumetry. We analyzed
the association between CMV serointensity and seropositivity with
hippocampal volume. We also explored the correlation between CMV
serointensity and seropositivity and CVLT scores.

RESULTS:

In both patient groups but not in controls, higher CMV serointensity was
significantly associated with smaller right hippocampal volume. Further,
in the group of patients with schizophrenia but not bipolar disorder,
CMV serointensity was negatively correlated with CVLT scores.

CONCLUSION:

CMV IgG titers are associated with decreased hippocampal volume and poorer
episodic verbal memory in patients with schizophrenia or bipolar
disorder. The mechanism of this association warrants further
exploration.

Immunosenescence is associated with human cytomegalovirus and shortened telomeres in type I bipolar disorder.

OBJECTIVE:

Bipolar disorder (BD) has been associated with
persistent low-grade inflammation and premature cell senescence, as
shown by reduced telomere length (TL). The human cytomegalovirus (CMV)
has increasingly been implicated in accelerated immunosenescence in
aging studies. Here, we compared CMV serology and its relationships with
cell senescence markers, including TL and lymphocyte subsets, in
patients with type I BD and healthy controls.

METHODS:

Twenty-two
euthymic female patients with BD type I and 17 age-matched healthy
controls were selected for the study. A sample of blood was collected
and mononuclear cells and DNA were isolated and TL measured. CMV
immunoglobulin M (IgM) and IgG titers were measured using
chemiluminescent assays. Lymphocyte subsets [T, natural killer (NK) and
NKT] were phenotyped by flow cytometry.

RESULTS:

Individuals
with BD had shorter TLs but higher CMV IgG levels than controls (both p
< 0.01). CMV IgG level was inversely correlated with TL. None of the
subjects showed IgM reactivity for CMV, excluding acute viral
infection. CMV IgG level was associated with expansion of senescent
CD8+CD28- T cells and NK cells, which are involved in viral control.

CONCLUSIONS:

These
data support the hypothesis of accelerated aging in BD, as shown by
shortened telomeres, higher seropositivity for CMV, and expansion of
senescent T cells.

Dorsal raphe neuroinflammation promotes dramatic behavioral stress dysregulation.

Impulsivity, risk-taking behavior, and elevated stress responsivity are
prominent symptoms of mania, a behavioral state common to schizophrenia
and bipolar disorder. Though inflammatory processes activated within the
brain are involved in the pathophysiology of both disorders, the
specific mechanisms by which neuroinflammation drives manic behavior are
not well understood. Serotonin cell bodies originating within the
dorsal raphe (DR) play a major role in the regulation of behavioral
features characteristic of mania. Therefore, we hypothesized that the
link between neuroinflammation and manic behavior may be mediated by
actions on serotonergic neurocircuitry. To examine this, we induced
local neuroinflammation in the DR by viral delivery of Cre recombinase
into interleukin (IL)-1β(XAT) transgenic male and female mice, resulting
in overexpressing of the proinflammatory cytokine, IL-1β. For assertion
of brain-region specificity of these outcomes, the prefrontal cortex
(PFC), as a downstream target of DR serotonergic projections, was also
infused. Inflammation within the DR, but not the PFC, resulted in a
profound display of manic-like behavior, characterized by increased
stress-induced locomotion and responsivity, and reduced
risk-aversion/fearfulness. Microarray analysis of the DR revealed a
dramatic increase in immune-related genes, and dysregulation of genes
important in GABAergic, glutamatergic, and serotonergic
neurotransmission. Behavioral and physiological changes were driven by a
loss of serotonergic neurons and reduced output as measured by
high-performance liquid chromatography, demonstrating
inflammation-induced serotonergic hypofunction. Behavioral changes were
rescued by acute selective serotonin reuptake inhibitor treatment,
supporting the hypothesis that serotonin dysregulation stemming from
neuroinflammation in the DR underlies manic-like behaviors.

Serological Documentation of Maternal Influenza Exposure and Bipolar Disorder in Adult Offspring

Objective
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.

Method
The study used a nested case-control design in the Child Health
and Development Study birth cohort. In all, 85 individuals with bipolar
disorder were identified following extensive ascertainment and
diagnostic assessment and matched to 170 comparison subjects in the
analysis. Serological documentation of maternal exposure to influenza
was determined using the hemagglutination inhibition assay.

Results
No association was observed between serologically documented
maternal exposure to influenza and bipolar disorder in offspring.
However, maternal serological influenza exposure was related to a
significant fivefold greater risk of bipolar disorder with psychotic
features.

Conclusions
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.

Markers of inflammation and stress distinguish subsets of individuals with schizophrenia and bipolar disorder.

Schizophrenia and bipolar disorder share a number of common features,
both symptomatically and biologically. Abnormalities in the neuroimmune
and the stress-signaling pathways have been previously identified in
brains of individuals with both diseases. However, the possible
relationship between abnormalities in stress and neuroimmune signaling
within the cortex of people with psychotic illness has not been defined.
To test the hypothesis that combined alterations in brain stress
responsiveness and neuroimmune/inflammatory status are characteristic of
some individuals suffering from major mental illness, we examined gene
expression in the Stanley Array Cohort of 35 controls, 35 individuals
with schizophrenia and 34 individuals with bipolar disorder. We used
levels of 8 inflammatory-related transcripts, of which SERPINA3 was
significantly elevated in individuals with schizophrenia (F(2,88)=4.137,
P<0.05), and 12 glucocorticoid receptor signaling (stress) pathway
transcripts previously examined, to identify two clusters of
individuals: a high inflammation/stress group (n=32) and a low (n=68)
inflammation/stress group. The high inflammation/stress group has a
significantly greater number of individuals with schizophrenia (n=15),
and a trend toward having more bipolar disorder individuals (n=11), when
compared with controls (n=6). Using these subgroups, we tested which
microarray-assessed transcriptional changes may be associated with high
inflammatory/stress groups using ingenuity analysis and found that an
extended network of gene expression changes involving immune, growth
factors, inhibitory signaling and cell death factors also distinguished
these groups. Our work demonstrates that some of the heterogeneity in
schizophrenia and bipolar disorder may be partially explained by
inflammation/stress interactions, and that this biological subtype cuts
across Diagnostic and Statistical Manual of Mental Disorders
(DSM)-defined categories.

Specific subcellular changes in oxidative stress in prefrontal cortex from patients with bipolar disorder.

Previously, we found decreased mitochondrial complex I subunits levels and increased protein oxidation and nitration in postmortem prefrontal cortex (PFC) from patients with bipolar disorder (BD) and schizophrenia (SCZ). The objectives of this study were to replicate our findings in an independent sample of subjects with BD, and to examine more specifically oxidative and nitrosative damage to mitochondrial and synaptosomal proteins and lipid peroxidation in myelin. We isolated mitochondria, synaptosomes, and myelin using a percoll gradient from postmortem PFC from patients with BD, SCZ, and healthy controls. Levels of mitochondrial complex I and III proteins, protein oxidation (carbonylation), and nitration (3-nitrotyrosine) were assessed using immunobloting analysis. Lipid peroxidation [lipid hydroperoxides (LPH), 8-isoprostane (8-Iso), 4-hydroxy-2-nonenal (4-HNE)] were measured using colorimetric or ELISA assays. We found decreased complex I subunits levels in BD subjects compared with control (CTL), but no difference in complex III subunits. Carbonylation was increased in synaptosomes from BD group while 3-nitrotyrosine was increased in mitochondria from BD and SCZ groups. 8-Iso was found increased in the BD group while 4-HNE was increased in both SCZ and BD when compared with controls with no differences in LPH. Our results suggest that in BD mitochondrial proteins are more susceptible to potentially reversible nitrosative damage while more longstanding oxidative damage occurs to synaptic proteins. Oxidative stress has been shown to be higher in the brain of patients with bipolar disorder (BD). Here, we demonstrated increased levels of protein oxidation in synaptosomes from postmortem prefrontal cortex from patients from BD group, while 3-nitrotyrosine was increased in mitochondria from BD and schizophrenia (SCZ) groups. Moreover, lipid peroxidation was found increased in the BD when compared with controls; suggesting that in BD mitochondrial proteins are more susceptible to potentially reversible nitrosative damage while more longstanding oxidative damage occurs to synaptic proteins.

Seroreactive marker for inflammatory bowel disease and associations with antibodies to dietary proteins in bipolar disorder.

 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.

METHODS:

We measured a marker of GI inflammation, anti-Saccharomyces cerevisiae antibodies (ASCA), in non-psychiatric controls (n = 207), in patients with bipolar disorder without a recent onset of psychosis (n = 226), and in patients with bipolar disorder with a recent onset of psychosis (n = 38). We compared ASCA levels to antibodies against gluten, casein, Epstein-Barr virus (EBV), herpes simplex virus 1 (HSV-1), influenza A, influenza B, measles, and Toxoplasma gondii.

RESULTS:

Elevated ASCA conferred a 3.5-4.4-fold increased odds ratio of disease association (age-, race-, and gender-corrected multinomial logistic regressions, p ≤ 0.00001) that was independent of type of medication received. ASCA correlated with food antibodies in both bipolar disorder groups (R2  = 0.29-0.59, p ≤ 0.0005), and with measles and T. gondii immunoglobulin G (IgG) in the recent onset psychosis bipolar disorder group (R2  = 0.31-0.36, p ≤ 0.004-0.01).

CONCLUSIONS:

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.