Forebrain-specific ablation of phospholipase Cγ1 causes manic-like behavior.

Manic episodes are one of the major diagnostic symptoms in a spectrum of neuropsychiatric disorders that include schizophrenia, obsessive-compulsive disorder and bipolar disorder (BD). Despite a possible association between BD and the gene encoding phospholipase Cγ1 (PLCG1), its etiological basis remains unclear. Here, we report that mice lacking phospholipase Cγ1 (PLCγ1) in the forebrain (Plcg1f/f; CaMKII) exhibit hyperactivity, decreased anxiety-like behavior, reduced depressive-related behavior, hyperhedonia, hyperphagia, impaired learning and memory and exaggerated startle responses. Inhibitory transmission in hippocampal pyramidal neurons and striatal dopamine receptor D1-expressing neurons of Plcg1-deficient mice was significantly reduced. The decrease in inhibitory transmission is likely due to a reduced number of γ-aminobutyric acid (GABA)-ergic boutons, which may result from impaired localization and/or stabilization of postsynaptic CaMKII (Ca2+/calmodulin-dependent protein kinase II) at inhibitory synapses. Moreover, mutant mice display impaired brain-derived neurotrophic factor-tropomyosin receptor kinase B-dependent synaptic plasticity in the hippocampus, which could account for deficits of spatial memory. Lithium and valproate, the drugs presently used to treat mania associated with BD, rescued the hyperactive phenotypes of Plcg1f/f; CaMKII mice. These findings provide evidence that PLCγ1 is critical for synaptic function and plasticity and that the loss of PLCγ1 from the forebrain results in manic-like behavior.

Immunoglobulin sub-class distribution in bipolar disorder and schizophrenia: potential relationship with latent Toxoplasma Gondii infection.

BACKGROUND: Immune dysfunction could play a significant role in the pathogenesis of bipolar disorder (BD) and schizophrenia (SZ), conditions with an underlying pro-inflammatory state. Studies on humoral immune responses (which reflects antibody mediated fight against pathogens) in schizophrenia and bipolar disorder are sparse and often providing contradictory results. The aim of this study was to assess humoral immunity in a group of stable bipolar disorder and schizophrenia patients compared to controls by determining total Immunoglobulins and IgG subclasses and to assess their association with latent Toxoplasma gondii and/or CMV infection. METHODS: 334 subjects (124 BD, 75 SZ and 135 Healthy Controls [HC]) were included and tested for humoral immunity by determining the total immunoglobulins (IgG,A and M) and IgG subclasses (IgG1, IgG2, IgG3, IgG4) and their relationship with latent Toxoplasma gondii infection, an established risk factor for BD and SZ. RESULTS: Although lower levels of IgG, IgG1, IgG2, IgG4 and IgA were found among BD as compared to HC and/or SZ, after adjustment for confounding variables, only low levels of IgG and IgG1 in BD remai- ned significant. Strikingly highest levels of antibodies to T. gondii (but not CMV) infection in BD and SZ were associated with lowest levels of IgG3 and IgG4 levels as compared to controls. CONCLUSIONS: Schizophrenia and bipolar disorder patients with latent T. gondii specific infection may be more vulnerable to changes in immuno-inflammatory processes than controls with similar latent infectious state. Simultaneous sequential immunological monitoring both in steady state and active disease phases in the same BD and SZ patients are warranted to understand the role of Toxoplasma gondii latency in these disorders.

Immune alterations in acute bipolar depression.

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.

Beyond the association. Toxoplasma gondii in schizophrenia, bipolar disorder, and addiction: systematic review and meta-analysis.

OBJECTIVE: To perform a meta-analysis on studies reporting prevalence of Toxoplasma gondii (T. gondii) infection in any psychiatric disorder compared with healthy controls. Our secondary objective was to analyze factors possibly moderating heterogeneity. METHOD: A systematic search was performed to identify studies into T. gondii infection for all major psychiatric disorders versus healthy controls. Methodological quality, publication bias, and possible moderators were assessed. RESULTS: A total of 2866 citations were retrieved and 50 studies finally included. Significant odds ratios (ORs) with IgG antibodies were found in schizophrenia (OR 1.81, P < 0.00001), bipolar disorder (OR 1.52, P = 0.02), obsessive-compulsive disorder (OR 3.4, P < 0.001), and addiction (OR 1.91, P < 0.00001), but not for major depression (OR 1.21, P = 0.28). Exploration of the association between T. gondii and schizophrenia yielded a significant effect of seropositivity before onset and serointensity, but not IgM antibodies or gender. The amplitude of the OR was influenced by region and general seroprevalence. Moderators together accounted for 56% of the observed variance in study effects. After controlling for publication bias, the adjusted OR (1.43) in schizophrenia remained significant. CONCLUSION: These findings suggest that T. gondii infection is associated with several psychiatric disorders and that in schizophrenia reactivation of latent T. gondii infection may occur.

Neonatal antibodies to infectious agents and risk of bipolar disorder: a population-based case-control study.

OBJECTIVE: There is a substantial evidence base linking prenatal exposure to infectious agents and an increased risk of schizophrenia. However, there has been less research examining the potential for these exposures to also contribute to risk for bipolar disorder. The aim of this study was to examine the association between neonatal markers of selected prenatal infections and risk for bipolar disorder. METHODS: Using population-based Danish registers, we examined 127 individuals with a diagnosis of bipolar disorder, and 127 sex and day-of-birth individually matched controls. Based on neonatal dried blood spots, we measured antibodies to herpes simplex virus type 1 (HSV-1) and 2 (HSV-2), cytomegalovirus (CMV), and Toxoplasma gondii. Relative risks were calculated for the matched pairs when examined for optical density units for antibodies to each of the infectious agents. RESULTS: There was no association between any of the neonatal markers of prenatal infection and risk of bipolar disorder. CONCLUSIONS: In contrast with studies of schizophrenia, our analysis does not support maternal infection with HSV-1, HSV-2, CMV, or Toxoplasma gondii as risk factors for bipolar disorder. However, larger study samples are needed, and data on, for example, specific serotypes of Toxoplasma and indicators of the timing of maternal infection are still warranted.

Serum antibodies to Toxoplasma gondii and Herpesvidae family viruses in individuals with schizophrenia and bipolar disorder: a case-control study.

BACKGROUND: Recent etiological studies for schizophrenia and bipolar disorder have focused on the protozoan Toxoplasma gondii and Herpesvirdae family viruses. OBJECTIVE: To determine the magnitude of T. gondii, cytomegalovirus (CMV), herpes simplex virus type 1 (HSV-1) and herpes simplex virus type 2 (HSV-2) infection in individuals with schizophrenia, bipolar disorder and healthy controls by using serologic diagnostic methods. MATERIAL AND METHODS: Serologic diagnostic method was used to determine the prevalence and level of antibodies to T gondii, CMV HSV-1 and HSV-2 in individuals with schizophrenia, bipolar disorder, and unaffected controls recruited from Butajira, Ethiopia. The study was conducted from March to May 2009. A total of 495 serum samples were analysed for the presence and level of immunoglobulin G (IgG) to T. gondii, CMV HSV-1, and HSV-2. RESULTS: The seroprevalence of T gondii infection was higher in individuals with schizophrenia [adjusted odds ratio = 4.7; 95% CI (1.5, 15.1)] and bipolar disorder [adjusted odds ratio = 3.0; 95% CI (1.1, 8.6)] than in unaffected controls. The level of IgG to CMV was also significantly higher in individuals with schizophrenia and bipoar disorder than in unaffected controls. Younger individuals with schizophrenia (< 25 years old) also had a significantly higher level of IgG to CMV than matched unaffected controls. CONCLUSION: This study provides additional evidence that infection with 7T gondii and CMV may be associated with some cases of schizophrenia and bipolar disorder. Additional studies should focus on antibodies to these agents in the sera and CSF of individuals with recent-onset psychosis.

Toxoplasma gondii antibody titers and history of suicide attempts in patients with recurrent mood disorders.

Toxoplasma gondii (T.gondii) is an obligate intracellular protozoan parasite infecting one-third of the world population, residing relatively silently in the brain of the immunocompetent host. We hypothesized that T.gondii seropositivity and serointensity are associated with having a history of attempting suicide and, in those attempting suicide, a greater number of attempts. T.gondii seropositivity and antibody titers were compared between (a) patients with recurrent mood disorders with history of suicide attempt (99 individuals) versus (b) patients with recurrent mood disorders without history of suicide attempt (119 individuals), and (c) healthy controls (39 individuals). Diagnosis was made using the Structured Clinical Interview for DSM-IV. Statistical methods included chi square, analysis of variance, and linear and logistic regression analyses. Suicide attempters had higher T.gondii antibody titers than nonsuicide attempters (p = 0.004). The logistic regression analysis revealed a predictive association between titers of anti- T.gondii antibodies and history of suicide attempt with OR = 1.55 (1.14-2.12), p = 0.006. No significant relationship was found between T.gondii seropositivity and suicide attempt status, number of prior suicide attempts, and recurrent mood disorder diagnosis. Although preliminary and bearing replication, this is the first report, to our knowledge, of an association between attempting suicide and T. gondii.

Lack of circulating toxoplasma gondii DNA in seropositive patients with bipolar or schizophrenia spectrum disorders.

Toxoplasmosis has been previously associated with an increased risk of having Schizophrenia or Bipolar disorder in several epidemiological studies. The aim of this observational, cross-sectional study was to examine the seroprevalence of Toxoplasma infection in a cohort of Italian psychiatric inpatients and to verify the presence of circulating Toxoplasma gondii DNA in the seropositive subjects. Sixty-three patients affected by bipolar or schizoaffective disorders according to DSM-5 criteria were enrolled. The presence of Toxoplasma infection was firstly examined using an indirect serological method (ELFA), and three different direct PCR-based methods were performed to detect circulating DNA in the seropositive patients. The seroprevalence of infection was 28.6%, with a significant association between higher age and the infection status. PCR, nested-PCR and Real-Time PCR revealed no positive samples for Toxoplasma gondii. This result is in contrast with recent data from case-control studies that detected parasite genome in patients with different neuropsychiatric diagnosis without clinical evidence of acute toxoplasmosis. Our findings are to be interpreted with caution, because of the small sample size, the heterogeneity of enrolled patients and the observational nature of the study. Further studies are needed to better define the clinical features correlated to the seropositive status in neuropsychiatric patients.

The association between antibodies to neurotropic pathogens and bipolar disorder : A study in the Dutch Bipolar (DB) Cohort and meta-analysis.

Exposure to neurotropic pathogens has been hypothesized to be a risk factor for the development of bipolar disorder (BD). However, evidence so far is inconsistent. We, therefore, analyzed the seroprevalence and titer levels of IgG antibodies against several herpesviruses and Toxoplasma gondii (T. gondii) in plasma of 760 patients with a bipolar disorder, 144 first-degree matched relatives and 132 controls of the Dutch Bipolar (DB) Cohort using ELISA. In addition, we performed a literature-based meta-analysis on the seroprevalence of IgG antibodies against these pathogens (n = 14). Our results in the DB Cohort and subsequent meta-analysis (n = 2364 BD patients, n = 5101 controls) show no association between exposure to herpesviruses and bipolar disorder (HSV-1 [adjusted OR 0.842, 95% CI 0.567-1.230], HSV-2 [adjusted OR 0.877, 95% CI 0.437-1.761], CMV [adjusted OR 0.884 95% CI 0.603-1.295], EBV [adjusted OR 0.968 95% CI 0.658-1.423]). In the DB Cohort, we did not find an association between bipolar disorder and T. gondii titer or seroprevalence either [adjusted OR 1.018, 95% CI 0.672-1.542]. The overall OR was not significant for T. gondii [OR: 1.4, 95% CI 0.95-1.90, p = 0.09), but subgroup analyses in age groups below 40 years showed a significantly increased seroprevalence of T. gondii IgGs in BD [OR: 1.8 (95% CI 1.10-2.89, p = 0.021]. Our meta-analysis indicates that T. gondii exposure may be a risk factor for BD in certain subpopulations.

Increased risk of bipolar disorder in patients with scabies: A nationwide population-based matched-cohort study.

Both scabies and bipolar disorder (BD) are common and troublesome disorders. There are several similarities in both diseases: pruritus, a higher prevalence in crowded environments, and cytokine-mediated inflammatory processes in the pathophysiology. We conducted this nationwide population-based study to investigate the possible relationship between scabies and BD. Based on the National Health Insurance Research Database (NHIRD) of Taiwan, a total of 7096 patients with scabies were identified as a study group and 28,375 matched patients as a control. We tracked the patients in both groups for a 7-year period to identify those newly diagnosed with BD. The demographic characteristics and comorbidities of the patients were analyzed, and Cox proportional hazard regressions were performed to calculate the hazard ratio (HR) of BD. Of the 35,471 patients in this study, 183 (0.5%) patients with newly diagnosed BD were identified, with 58 (0.8%) from the scabies group and 125 (0.4%) from the control group. The patients with scabies had a higher risk of subsequent BD, with a crude hazard ratio of 1.86 and an adjusted hazard ratio of 1.55 (95% confidence interval: 1.12-2.09, P < 0.05). This study shows there is an increased risk for BD among patients with scabies. Immunopathology may contribute to this association.

Infection and inflammation in schizophrenia and bipolar disorder.

The present study investigated the relationship between exposure to infectious agents and inflammation markers in individuals with schizophrenia (SZ), bipolar disorder (BP), and controls without a psychiatric disorder. We measured plasma levels of antibodies and innate immune markers and correlated them with clinical symptoms and cognitive function. In both SZ and BP, we found an increase in soluble CD14, and in BP an increase in C-reactive protein, IgM class antibodies against cytomegalovirus (CMV), and IgG class antibodies against herpes simplex virus 2. Furthermore in BP, we observed a negative relationship between IgG antibodies against CMV and scores for cognitive function.

Are treatment emergent suicidality and decreased response to antidepressants in younger patients due to bipolar disorder being misdiagnosed as unipolar depression?

While antidepressants have been demonstrated to be a safe and effective treatment for unipolar major depressive disorder (MDD) in adults, the use of antidepressants to treat children and adolescents is controversial. There is a paucity of evidence to suggest that antidepressants are effective when used to treat children and adolescents and some recent placebo-controlled evidence has suggested that antidepressant treatment increases suicidality in this population. MDD is a very broad construct, and includes many clinical subtypes. Bipolar Disorder (BD) has an earlier age of onset than MDD. The initial polarity of illness in bipolar disorder is frequently depression. Patients are more likely to first present for treatment during the depressive phase of the illness than during manic or hypomanic phases. It is probable that a substantial portion of depressed children and adolescents may not suffer from unipolar MDD but may have a bipolar spectrum disorder. There are few trials supporting the efficacy of antidepressants in bipolar disorder, and some evidence that they may induce rapid cycling, switching and mania. Antidepressant induced mania is often mixed, with admixtures of manic and depressive features. An increased suicide risk is a particular feature of mixed states, potentially explaining why suicidal ideation can emerge with antidepressant treatment. Antidepressants are unlikely to somehow act differently in children than they do in adults. A more plausible explanation is that incipient bipolar disorder is often not diagnosed early in children and adolescents and the differential effects of antidepressants in this group is a result of differing diagnostic casemixes.

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.

[Rapid cycle bipolar disorder: the present situation]. / Troubles bipolaires à cycles rapides: situation actuelle.

In 1974, rapid cycling bipolar disorder has been defined by Dunner and Fieve as four or more episodes of depression or mania per year. Twenty year later, this definition appeared for the first line in an international classification of mental disorders in the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders. The rapid cycling phenomenon has been since studied with new adapted modified criteria taking into account different duration of affective episodes which characterise rapid cycling. Rapid cycling is associated with a low prophylactic efficacy of lithium and often represents a difficult approach for the clinician. Clinical aspects, influence of antidepressants associated with acceleration of cycles and possible therapeutic trials including non pharmaceutical treatment are discussed.

[Reactivity of toxoplasmin intradermal test in neurotic and manic-depressive patients]. / Reactividad a la prueba intradérmica con toxoplasmina en enformos neuróticos y psicóticos maniacodepresivos.

Fifty patients with manic-depressive psychosis, 120 neurotics and 100 healthy individuals were studied. They underwent the toxoplasmin intradermal test. The highest percentage of reactors was found among patients with manic-depressive psychosis (66,0%). Patients with depressive neurosis accounted for the highest number among neurotics (55,6%). The intensity of reaction was higher among patients with manic-depressive psychosis. Neurotic patients were compared to schizophrenic patients from a previous study conducted by one out of the authors. It is concluded that the percentage of reactors is higher among patients with depressive mental disorders, and also that this percentage increases with mental deterioration in patients.

[Effective response to risperidone treatment in manic syndrome secondary to neurocysticercosis]. / Buena respuesta a risperidona en fase maniaca secundaria a neurocisticercosis.

This study presents a clinical case about a patient suffering a manic syndrome secondary to neurocysticercosis and no responding to traditional neuroleptic treatment. We administrated the risperidone treatment, that was effective.