[Show abstract][Hide abstract] ABSTRACT: Objective
Immunologic abnormalities have been found in bipolar disorder but pentraxin 3, a marker of innate immunity, has not been studied in this population.Methods
Levels of pentraxin 3 were measured in individuals with bipolar disorder, schizophrenia, and non-psychiatric controls. Linear regression models were used to compare the pentraxin 3 levels in each of the psychiatric groups to that in the control group, adjusting for demographic and clinical variables. Logistic regression models were used to calculate the odds ratios associated with levels of pentraxin 3 which differed from specified levels of the control group.ResultsThe sample consisted of 831 individuals: 256 with bipolar disorder, 309 with schizophrenia, and 266 without a psychiatric disorder. The levels of pentraxin 3 in the bipolar disorder, but not in the schizophrenia, group were significantly lower than those of controls, adjusting for age, gender, race, maternal education, smoking status, and body mass index (t = −3.78, p < 0.001). The individuals with bipolar disorder also had significantly increased odds of having low levels of pentraxin 3 relative to both the 10th and 25th percentile level of the controls and significantly decreased odds of having a level greater than the 75th and the 90th percentile level of the controls, adjusting for the same covariates.Conclusions
Individuals with bipolar disorder have low levels of pentraxin 3 which may reflect impaired innate immunity. An increased understanding of the role of innate immunity in the etiopathogenesis of bipolar disorder might lead to new modalities for the diagnosis and treatment of this disorder.
[Show abstract][Hide abstract] ABSTRACT: Chloroviruses (family Phycodnaviridae) are large DNA viruses known to infect certain eukaryotic green algae and have not been previously shown to infect humans or to be part of the human virome. We unexpectedly found sequences homologous to the chlorovirus Acanthocystis turfacea chlorella virus 1 (ATCV-1) in a metagenomic analysis of DNA extracted from human oropharyngeal samples. These samples were obtained by throat swabs of adults without a psychiatric disorder or serious physical illness who were participating in a study that included measures of cognitive functioning. The presence of ATCV-1 DNA was confirmed by quantitative PCR with ATCV-1 DNA being documented in oropharyngeal samples obtained from 40 (43.5%) of 92 individuals. The presence of ATCV-1 DNA was not associated with demographic variables but was associated with a modest but statistically significant decrease in the performance on cognitive assessments of visual processing and visual motor speed. We further explored the effects of ATCV-
Proceedings of the National Academy of Sciences 10/2014; · 9.81 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: A number of infectious and inflammatory markers have been associated with schizophrenia but previous investigations have not yielded definitive conclusions. We examined multiple antibodies to infectious agents and food antigens as well as protein markers of inflammation in well-characterized individuals with a recent onset of psychosis (N = 106), persistent schizophrenia (N = 261), and controls (N = 233). Linear regression methods were used to calculate the association between the markers in both patient groups in comparison with controls adjusting for demographic factors. For the recent onset group, significant associations were found for IgG antibodies to measles (t = 8.31, p < .001), gliadin (t = 5.90, p < .001), bovine casein (t = 4.74, p < .001), human coronavirus (t = 2.89, p = .004), Toxoplasma gondii (t = 2.20, p = .029), and the group D retroviruses, Mason-Pfizer monkey virus (t = 3.97, p < .001) and murine leukemia virus (t = 3.27, p = .001). For the persistent schizophrenia group, significant associations were found for C-reactive protein (t = 7.47, p ⩽ .001); IgG antibodies to wheat gliadin (t = 2.58, p = .010), Saccharomyces cerevisiae (t = −2.78, p < .006), measles (t = 2.37, p = .018), Herpes simplex virus (HSV) type 2 (t = 2.56, p = .011), and human coronavirus (t = 2.67, p = .008). No significant case-control differences were found for antibodies to cytomegalovirus, HSV-1, Epstein-Barr Virus, varicella-zoster virus, or influenza viruses. These results indicate overlap between the markers found in recent onset psychosis and in persistent schizophrenia. Future studies that assess patients throughout the course of the illness may further identify the infectious and inflammatory factors that contribute to disease pathogenesis.
Brain Behavior and Immunity 09/2014; 40:e6. · 5.61 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Increased rates of exposure to Toxoplasma gondii have been found in individuals with schizophrenia and bipolar disorder, but the association between Toxoplasma and cognitive functioning has not previously been examined. We measured IgG and IgM class antibodies to Toxoplasma in 408 nonelderly individuals with schizophrenia, 347 with bipolar disorder, and 352 nonpsychiatric controls. Cognitive functioning was measured with the Repeatable Battery for the Assessment of Neuropsychological Status. Multivariate linear and regression analyses showed significant associations between Toxoplasma IgM antibody level and cognitive scores within the control group and the bipolar disorder group but not the schizophrenia group. Within the control group, having an elevated Toxoplasma IgM antibody level, greater than or equal to the 50th and 75th levels of the control group, was associated with significantly elevated odds of a low total cognitive score. Exposure to Toxoplasma may confer risk for lower cognitive functioning in persons without a psychiatric disorder and those with bipolar disorder.
[Show abstract][Hide abstract] ABSTRACT: Background
Cognitive deficits are a central feature of schizophrenia but it is not certain how cognitive functioning changes over time. The purpose of this prospective longitudinal study was to determine the temporal change of cognitive functioning and the predictors of cognitive performance from among demographic, clinical, and biological variables.
Participants were individuals with schizophrenia or schizoaffective disorder whose cognitive functioning was assessed at multiple time points with the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). At the baseline visit participants had a blood sample drawn from which C-reactive protein, antibodies to Herpes Simplex Virus type 1, and selected genetic polymorphisms were measured. Repeated measures linear regression was used to determine whether cognitive measures changed over time and which variables predicted cognitive performance.
The sample consisted of 132 participants, mean age 43.7 years at baseline, who received a median of 3 cognitive assessments over a period averaging 2.8 years. The RBANS Total score and Language index showed no statistically significant temporal change; performance on two indices, Immediate Memory and Attention, showed modest but statistically significant improvements (gains of 0.89 ± 0.33 and 0.76 ± 0.29 points per year, respectively); Visuospatial/Constructional performance showed a modest but statistically significant decline (of 0.80 ± 0.25 points per year). Few variables predicted cognitive performance; however greater psychiatric symptom severity was associated with worse cognitive performance for most cognitive measures.
Cognitive functioning in middle-aged persons with schizophrenia showed an absence of decline for most measures and modest gains in some measures.
Schizophrenia Research 07/2014; · 4.43 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background / Purpose:
Many studies have found that viral infections like Herpes Simplex Virus 1 (HSV-1) are associated with cognitive impairment in schizophrenia as well as healthy controls. It has also been shown that daily functioning is affected by our cogniton level. The present study looked at whether HSV-1 infection affects daily living skills in schizophrenia.
Some domains of daily living skills were impaired in HSV-1 exposed persons with schizophrenia.
69th Society of Biological Psychiatry Annual Meeting 2014; 06/2014
[Show abstract][Hide abstract] ABSTRACT: The Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) and Treatment Units for Research on Neurocognition and Schizophrenia projects were designed to facilitate the development of new drugs for the treatment of cognitive impairments in people with schizophrenia. The MATRICS project identified three drug mechanisms of particular interest: dopaminergic, cholinergic, and glutamatergic. As a group, while people with schizophrenia have moderate cognitive impairment, it is the best predictor of long-term outcome. Unfortunately, there are no approved medications for cognitive impairment in this population. Hence, the development of new pharmacological approaches is critical for reducing illness-related disability. The combination of an acetylcholinesterase inhibitor (AChEI) and memantine is more effective than either medication alone to improve cognition in Alzheimer's dementia. Galantamine is not only an AChEI, but also a positive allosteric modulator of the α4β2 and α7 nicotinic receptors. Hypofunction of N-methyl-d-aspartate (NMDA) receptors has been implicated in the pathophysiology of cognitive symptoms in schizophrenia and hence memantine may positively impact cognition. Memantine decreases the tonic NMDA current and galantamine enhances the action potential mediated by a postsynaptic NMDA current. This results in an increased signal transmission; therefore, a greater signal-to-noise ratio occurs with the combination than memantine alone. Galantamine improves the α-amino-3-hydroxy-5-methyl-4-isoxazol-propionate (AMPA)-mediated signaling which could be neuroprotective and may improve memory coding. The combination of galantamine and memantine may be particularly effective in schizophrenia in order to increase the selective cognition enhancement produced by either medication alone. In the future, multitarget-directed ligands may play a role in the treatment of complex diseases like schizophrenia.
Schizophrenia Research 05/2014; · 4.43 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Elevated levels of antibodies to Cytomegalovirus (CMV) have been associated with cognitive impairment, but the quantitative relationship between CMV antibody levels and domains of cognitive functioning in younger adults has not been established.
PLoS ONE 05/2014; 9(5):e95510. · 3.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Objective: A range of immune system abnormalities have been associated with schizophrenia. Probiotic compounds modulate the immune response and offer a potential treatment strategy for schizophrenia. Probiotic compounds have also been observed to improve gastrointestinal dysfunction, which is a common problem in individuals with schizophrenia. We performed a randomized, double-blind, placebo-controlled trial to examine whether probiotic supplementation can reduce symptom severity in patients with schizophrenia receiving antipsychotic treatment and also whether probiotics are associated with bowel functioning. Methods: Outpatients with schizophrenia (N = 65) meeting DSM-IV criteria and with at least moderately severe psychotic symptoms were enrolled in the study from December 2010-August 2012. Following a 2-week placebo run-in period, patients were randomly assigned to 14 weeks of double-blind adjunctive probiotic (combined Lactobacillus rhamnosus strain GG and Bifidobacterium animalis subsp. lactis strain Bb12) or placebo therapy. Psychiatric symptoms were assessed biweekly with the Positive and Negative Syndrome Scale (PANSS), and patients were queried weekly about their gastrointestinal functioning. Results: Repeated-measures analysis of variance showed no significant differences in the PANSS total score between probiotic and placebo supplementation (F = 1.28, P = .25). However, patients in the probiotic group were less likely to develop severe bowel difficulty over the course of the trial (hazard ratio = 0.23; 95% CI, 0.09-0.61, P = .003). Conclusions: Probiotic supplementation may help prevent a common somatic symptom associated with schizophrenia. Trial Registration: ClinicalTrials.gov identifier: NCT01242371.
The primary care companion to CNS disorders. 02/2014; 16(1).
[Show abstract][Hide abstract] ABSTRACT: Our understanding of bipolar disorder (BD) aetiology has advanced in recent years but our ability to translate this to improve patient care in the clinic is still limited.
In this study, we have measured the concentrations of 190 different molecules using sensitive multiplex immunoassays in plasma of 17 BD patients compared to 46 matched control subjects.
The analyses led to the identification of 26 dysregulated proteins in BD patients compared to controls. These molecules were comprised mostly of growth factors, hormones, lipid transport and inflammatory proteins. Decreased apolipoprotein A1 has previously been associated with BD patients and this was confirmed in our study.
The present pilot study was limited by its small sample size, use of multiple drug treatments and the lack of dietary restrictions at the time of sampling.
Future studies may increase our understanding of BD which will help to pave the way for much-needed patient stratification for better treatment outcomes.
Journal of Affective Disorders 12/2013; · 3.76 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 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.
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.
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 (R(2) = 0.29-0.59, p ≤ 0.0005), and with measles and T. gondii immunoglobulin G (IgG) in the recent onset psychosis bipolar disorder group (R(2) = 0.31-0.36, p ≤ 0.004-0.01).
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.
[Show abstract][Hide abstract] ABSTRACT: Introduction: 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.
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 serointensitiy and seropositivity and CVLT scores.
In both patients 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.
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.
Progress in Neuro-Psychopharmacology and Biological Psychiatry 09/2013; · 4.03 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 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.
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.
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).
Infection with T. gondii may confer risk for mania.
[Show abstract][Hide abstract] ABSTRACT: Markers of immune activation have been associated with mania but have not been examined in combination. We studied the association between mania and an inflammation score based on four immune markers.
A total of 57 individuals with mania were assessed at up to three time points: the day of hospital admission, evaluation several days later, and six-month follow-up. Also assessed were 207 non-psychiatric controls and 330 individuals with recent onset psychosis, multi-episode schizophrenia, or bipolar disorder depression. A combined inflammation score was calculated by factor analysis of the levels of class-specific antibodies to the NR peptide of the NMDA receptor; gliadin; Mason-Pfizer monkey virus protein 24; and Toxoplasma gondii. Inflammation scores among groups were compared by multivariate analyses. The inflammation score of the mania group at evaluation was studied as a predictor of re-hospitalization in the follow-up period.
The combined inflammation score of the mania group at hospital admission and at evaluation differed significantly from that of the non-psychiatric controls (t = 3.95, 4.10, p<.001). The inflammation score was significantly decreased at six month follow-up (F = 5.85, p = 0.004). There were not any significant differences in the inflammation scores of any of the other psychiatric groups and that of the controls. Within the mania group, an elevated inflammation score at evaluation predicted re-hospitalization (Hazard ratio = 7.12, p = .005).
Hospitalization for mania is associated with immune activation. The level of this activation is predictive of subsequent re-hospitalization. Interventions for the modulation of inflammation should be evaluated for the therapy of individuals with mania.
PLoS ONE 09/2013; 8(9):e73520. · 3.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Prolactin elevations occur in people treated with antipsychotic medications and are often much higher in women than in men. Hyperprolactinemia is known to cause amenorrhea, oligomenorrhea, galactorrhea and gynecomastia in females and is also associated with sexual dysfunction and bone loss. These side effects increase risk of antipsychotic nonadherence and suicide and pose significant problems in the long term management of women with schizophrenia. In this manuscript, we review the literature on prolactin; its physiology, plasma levels, side effects and strategies for treatment. We also present the rationale and protocol for an ongoing clinical trial to treat symptomatic hyperprolactinemia in premenopausal women with schizophrenia. More attention and focus are needed to address these significant side effects and help the field better personalize the treatment of women with schizophrenia.
[Show abstract][Hide abstract] ABSTRACT: Persons with schizophrenia have a reduced life expectancy largely due to death from natural causes. Factors that have been previously associated with excess mortality include cigarette smoking and antipsychotic medication. The role of other environmental factors such as exposure to infectious agents has been the subject of only limited investigation. We prospectively assessed a cohort of persons with schizophrenia with a clinical evaluation and a blood sample from which antibodies to human herpes viruses and Toxoplasma gondii were measured. Mortality was determined with data from the National Death Index following a period of up to 11 years. We examined the role of demographic, serological, and clinical factors on mortality. A total of 25 (5%) of 517 persons died of natural causes. The standardized mortality ratio was 2.80 (95% CI 0.89, 6.38). After adjusting for age and gender, mortality from natural causes was predicted in separate models by cigarette smoking (relative risk [RR] = 4.66, P = .0029); lower cognitive score (RR = 0.96, P = .013); level of antibodies to Epstein-Barr virus (RR = 1.22, P = .0041) and to Herpes Simplex virus type 1 (RR = 1.19, P = .030); immunologic disease (RR = 3.14, P = .044); and genitourinary disease (RR = 2.70; P = .035). Because cigarette smoking confers an almost 5-fold risk of mortality, smoking cessation is an urgent priority. Having an elevated level of antibodies to Epstein-Barr virus and to Herpes Simplex virus type 1 are also significant predictors of death from natural causes.