The puzzle of quality of life in schizophrenia: putting the pieces together with the FACE-SZ cohort.

BACKGROUND: The determinants of quality of life (QoL) in schizophrenia are largely debated, mainly due to methodological discrepancies and divergence about the concepts concerned. As most studies have investigated bi- or tri-variate models, a multivariate model accounting for simultaneous potential mediations is necessary to have a comprehensive view of the determinants of QOL. We sought to estimate the associations between cognitive reserve, cognition, functioning, insight, depression, schizophrenic symptoms, and QoL in schizophrenia and their potential mediation relationships. METHODS: We used structural equation modeling with mediation analyses to test a model based on existing literature in a sample of 776 patients with schizophrenia from the FondaMental Foundation FACE-SZ cohort. RESULTS: Our model showed a good fit to the data. We found better functioning to be positively associated with a better QoL, whereas better cognition, better insight, higher levels of depression, and schizophrenic symptoms were associated with a lower QoL in our sample. Cognitive reserve is not directly linked to QoL, but indirectly in a negative manner via cognition. We confirm the negative relationship between cognition and subjective QoL which was previously evidenced by other studies; moreover, this relationship seems to be robust as it survived in our multivariate model. It was not explained by insight as some suggested, thus the mechanism at stake remains to be explained. CONCLUSION: The pathways to subjective QoL in schizophrenia are complex and the determinants largely influence each other. Longitudinal studies are warranted to confirm these cross-sectional findings.

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.

Direct medical cost of bipolar disorder: Insights from the FACE-BD longitudinal cohort.

BACKGROUND: Bipolar disorder (BD) is a severe chronic psychiatric disorder affecting 0.5 to 1% of the population worldwide. To date, most studies have estimated the cost of BD via information sourced from insurance claims with limited information on clinical characteristics and course of BD. The aims of this study are (i) to estimate the direct healthcare cost associated with BD and to identify contributing factors and (ii) to study the evolution of cost during a two-year follow-up period. METHOD: We analyzed a sample of 1116 individuals with BD included in the Advanced Centers of Expertise in Bipolar Disorder cohort. We estimated the direct healthcare cost per year and per patient, and we identified the clinical features of patients with BD associated with higher direct healthcare costs. In a subsample of patients followed up for two years centers of expertise for BD, we studied the evolution of direct healthcare cost. RESULTS: The average cost of bipolar disorder was € 6910 per year and per patient. Clinical features of BD, sociodemographic characteristics, and associated addiction were associated with higher direct healthcare costs. In the subsample of patients followed-up for two years, direct healthcare cost dropped by more than 50%, strongly suggesting the beneficial effect of specialized care organization. LIMITATION: We did not estimate indirect healthcare and intangible costs. CONCLUSION: Our study investigates the cost of BD and its evolution in a deeply phenotyped longitudinal sample. Cost-utility and cost-effectiveness analyses are required to inform resource allocation decisions and to promote innovative healthcare organizations.

Overlap and Mutual Distinctions Between Clinical Recovery and Personal Recovery in People With Schizophrenia in a One-Year Study.

Recovery is a multidimensional construct that can be defined either from a clinical perspective or from a consumer-focused one, as a self-broadening process aimed at living a meaningful life beyond mental illness. We aimed to longitudinally examine the overlap and mutual distinctions between clinical and personal recovery. Of 1239 people with schizophrenia consecutively recruited from the FondaMental Advanced Centers of Expertise for SZ network, the 507 present at one-year did not differ from those lost to follow-up. Clinical recovery was defined as the combination of clinical remission and functional remission. Personal recovery was defined as being in the rebuilding or in the growth stage of the Stages of Recovery Instrument (STORI). Full recovery was defined as the combination of clinical recovery and personal recovery. First, we examined the factors at baseline associated with each aspect of recovery. Then, we conducted multivariable models on the correlates of stable clinical recovery, stable personal recovery, and stable full recovery after one year. At baseline, clinical recovery and personal recovery were characterized by distinct patterns of outcome (i.e. better objective outcomes but no difference in subjective outcomes for clinical recovery, the opposite pattern for personal recovery, and better overall outcomes for full recovery). We found that clinical recovery and personal recovery predicted each other over time (baseline personal recovery for stable clinical recovery at one year; P = .026, OR = 4.94 [1.30-23.0]; baseline clinical recovery for stable personal recovery at one year; P = .016, OR = 3.64 [1.31-11.2]). In short, given the interaction but also the degree of difference between clinical recovery and personal recovery, psychosocial treatment should target, beyond clinical recovery, subjective aspects such as personal recovery and depression to reach full recovery.

Immune Signatures of Treatment-Resistant Schizophrenia: A FondaMental Academic Centers of Expertise for Schizophrenia (FACE-SZ) Study.

Treatment-resistant schizophrenia (TRS) affects around 30% of patients with schizophrenia (SZ) resulting in poor functioning, relapses, and reduced quality of life. Convergent findings show that inflammation could contribute to resistance. We thus search for immune signatures of patients with TRS/ultra TRS (UTRS) in a sample of community-dwelling outpatients with SZ. In total, 195 stabilized SZ patients (mean age = 31.2 years, 73% male gender) were consecutively included in the network of the FondaMental Expert Centers for Schizophrenia in France and received a thorough clinical assessment. At inclusion, psychotic symptomatology was evaluated by the Positive and Negative Syndrome Scale (PANSS) for schizophrenia. Circulating serum/plasma levels of a large panel of markers reflecting the main inflammatory pathways were evaluated. TRS was defined by current treatment by clozapine (CLZ) and UTRS by current CLZ treatment + PANSS total score ≥ 70. The frequency of TRS and UTRS patients was, respectively, 20% and 7.7% and was defined using multivariable analysis elevated by high levels of interleukin (IL)-12/IL-23p40, IL-17A, IL-10, and beta 2 microglobulin (B2M) and IL-12/IL-23p40, IL-17A, IL-6, IL-10, IFNγ, and B2M, respectively. These observations suggest that resistance and ultra resistance to CLZ treatment are underpinned by pro-inflammatory molecules mainly belonging to the T helper 17 pathway, a finding making sense given the interplay between inflammation and antipsychotic treatment responses. If confirmed, our findings may allow us to consider IL-23/IL-17 pathway as a therapeutic target for patients with resistance to antipsychotics.

Precision psychiatry with immunological and cognitive biomarkers: a multi-domain prediction for the diagnosis of bipolar disorder or schizophrenia using machine learning.

Precision psychiatry is attracting increasing attention lately as a recognized priority. One of the goals of precision psychiatry is to develop tools capable of aiding a clinically informed psychiatric diagnosis objectively. Cognitive, inflammatory and immunological factors are altered in both bipolar disorder (BD) and schizophrenia (SZ), however, most of these alterations do not respect diagnostic boundaries from a phenomenological perspective and possess great variability in different individuals with the same phenotypic diagnosis and, consequently, none so far has proven to have the ability of reliably aiding in the differential diagnosis of BD and SZ. We developed a probabilistic multi-domain data integration model consisting of immune and inflammatory biomarkers in peripheral blood and cognitive biomarkers using machine learning to predict diagnosis of BD and SZ. A total of 416 participants, being 323, 372, and 279 subjects for blood, cognition and combined biomarkers analysis, respectively. Our multi-domain model performances for the BD vs. control (sensitivity 80% and specificity 71%) and for the SZ vs. control (sensitivity 84% and specificity 81%) pairs were high in general, however, our multi-domain model had only moderate performance for the differential diagnosis of BD and SZ (sensitivity 71% and specificity 73%). In conclusion, our results show that the diagnosis of BD and of SZ, and that the differential diagnosis of BD and SZ can be predicted with possible clinical utility by a computational machine learning algorithm employing blood and cognitive biomarkers, and that their integration in a multi-domain outperforms algorithms based in only one domain. Independent studies are needed to validate these findings.

Effects of Cumulative Herpesviridae and Toxoplasma gondii Infections on Cognitive Function in Healthy, Bipolar, and Schizophrenia Subjects.

OBJECTIVE: Schizophrenia and bipolar disorder are associated with cognitive impairment leading to social disruption. While previous studies have focused on the effect of individual infectious exposure, namely, Herpesviridae viruses or Toxoplasma gondii (T gondii), on cognitive functioning, the objective of the present study was to examine the effect of multiple infections on cognitive functioning in patients with schizophrenia and bipolar disorder and in healthy controls. METHODS: Seropositivity to herpes simplex virus type 1 (HSV-1), herpes simplex virus type 2 (HSV-2), cytomegalovirus (CMV), and T gondii was related to cognitive status among 423 participants (recruited between 2008 and 2014; 138 patients with bipolar disorder, 105 patients with schizophrenia [DSM-IV criteria], and 180 healthy controls) for episodic verbal memory (California Verbal Learning Test), working memory (Wechsler Adult Intelligence Scale, third edition), and premorbid intelligence quotient (National Adult Reading Test). RESULTS: Seropositivity to and antibody levels of HSV-1 were significantly associated with working memory, which persisted after correction (backward digit span: ß = -0.10 [0.05], χ² = 33.89, P = .0001) in the overall sample. This association was particularly strong in the control group (ß = -0.18 [0.08], P = .04, Z = -3.55, P = .0008; corrected P = .012). Further, cumulative exposure to HSV-1, HSV-2, and CMV viruses and T gondii parasite was also associated with lower scores on working memory as measured by backward digit span in the overall sample (Z = 2.86, P = .004; Z = 2.47, P = .01; and Z = 3.35, P = .01, respectively). CONCLUSIONS: Exposures to Herpesviridae and T gondii parasite seem to impact cognitive functioning. Because infections caused by Herpesviridae and/or T gondii parasite are quite common in the (general) population, assessing and confirming the cognitive impairment among those who have cumulative exposures is useful and of interest.

Treatment with anti-toxoplasmic activity (TATA) for toxoplasma positive patients with bipolar disorders or schizophrenia: a cross-sectional study.

OBJECTIVE: 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.