Serum claudin-5 levels among patients with unipolar and bipolar depression in relation to the pro-inflammatory cytokine tumor necrosis factor-alpha levels.

Accumulating evidence indicates that inflammation and neurovascular unit (NVU) dysfunction contribute to depression via disrupted blood-brain barrier (BBB) integrity. Claudin-5, an endothelial tight-junction protein expressed in the NVU and contributing to BBB integrity, has been implicated in psychiatric disorders, including major depressive disorder (MDD) and schizophrenia. In an animal model of depressive-like behavior, the pro-inflammatory cytokine tumor necrosis factor-alpha (TNF-α) was found to affect BBB permeability and claudin-5 expression of NVU endothelial cells. To the best of the authors' knowledge, this study is the first to assess the relationship between serum claudin-5 and TNF-α levels, during major depressive episodes (MDEs). Serum levels of claudin-5 and TNF-α of 40 patients diagnosed with current MDE [19 with MDD and 21 with bipolar disorder (BD)] and 28 matched healthy controls (HCs) were analyzed. Claudin-5 and TNF-α serum levels in the MDE group were significantly higher than in the HC one. Discrete analysis according to MDE type indicated significantly increased claudin-5 serum levels in BD but not in MDD patients, compared to HCs, even after controlling for confounders. In the MDE group, a significant positive correlation was found between claudin-5 and TNF-α serum levels. In complementary analysis, serum levels of the pro-inflammatory cytokine interleukin-6 were significantly higher among MDE patients compared to HCs, however, no significant correlation was found with claudin-5 levels. In conclusion, as indicated by preclinical studies, our clinical study suggests a possible specific interaction between the NVU/BBB marker claudin-5 and the inflammatory marker TNF-α in the pathogenesis of depression.

Development and validation of a machine learning-based postpartum depression prediction model: A nationwide cohort study.

BACKGROUND: Currently, postpartum depression (PPD) screening is mainly based on self-report symptom-based assessment, with lack of an objective, integrative tool which identifies women at increased risk, before the emergent of PPD. We developed and validated a machine learning-based PPD prediction model utilizing electronic health record (EHR) data, and identified novel PPD predictors. METHODS: A nationwide longitudinal cohort that included 214,359 births between January 2008 and December 2015, divided into model training and validation sets, was constructed utilizing Israel largest health maintenance organization's EHR-database. PPD was defined as new diagnosis of a depressive episode or antidepressant prescription within the first year postpartum. A gradient-boosted decision tree algorithm was applied to EHR-derived sociodemographic, clinical, and obstetric features. RESULTS: Among the birth cohort, 1.9% (n = 4104) met the case definition of new-onset PPD. In the validation set, the prediction model achieved an area under the curve (AUC) of 0.712 (95% confidence interval, 0.690-0.733), with a sensitivity of 0.349 and a specificity of 0.905 at the 90th percentile risk threshold, identifying PPDs at a rate more than three times higher than the overall set (positive and negative predictive values were 0.074 and 0.985, respectively). The model's strongest predictors included both well-recognized (e.g., past depression) and less-recognized (differing patterns of blood tests) PPD risk factors. CONCLUSIONS: Machine learning-based models incorporating EHR-derived predictors, could augment symptom-based screening practice by identifying the high-risk population at greatest need for preventive intervention, before development of PPD.

Lack of association between unipolar or bipolar depression and serum aquaporin-4 autoantibodies.

Aquaporin-4 (AQP4), an astrocyte water channel protein, is the target antigen of serum immunoglobulin G (IgG) autoantibody in neuromyelitis optica spectrum disorders (NMOsd), a group of inflammatory, demyelinating diseases of the central nervous system. Recently, a reduction in blood vessels coverage by AQP4-immunoreactive astrocytes was demonstrated in depressed patients, indicating a role for AQP4 in mood disorders. Moreover, a possible association between depression and serum AQP4-IgG was suggested in a case report of a treatment resistant depression (TRD) patient diagnosed with NMOsd with positive serum AQP4 autoantibodies. We investigated, for the first time, the presence of serum AQP4-IgG in patients with unipolar and bipolar depression and healthy controls (HCs). In this multicenter study, 25 major depressive disorder (MDD) and 25 bipolar disorder (BD) patients, during an acute major depressive episode (MDE), and 30 matched HCs were screened for the presence of serum AQP4-IgG, using a cell-based assay. The MDE patients underwent a repeated AQP4-IgG assessment at a 3-month follow-up visit. The MDE group (N = 50) had illness duration of 12.7 years (SD = 10.5), 12% of them were psychotropic medication-free and 26% were defined as TRD. All MDE patients and HCs, including three BD patients who experienced a manic switch, were seronegative for AQP4-IgG at baseline and follow-up assessments. In conclusion, contrary to our hypothesis, AQP4 autoantibodies were not detected in serum of unipolar and bipolar depressed patients. However, AQP4 may still play a role in the pathogenesis of mood disorders through different mechanisms of action such as altered brain AQP4 expression.

Nonfunctional Redundant Acts Characterize OCD, Even in OCD-Unrelated Tasks: A Demonstration in Questionnaire Completion.

BACKGROUND: Ethological methods used to analyze human obsessive-compulsive disorder (OCD) rituals demonstrated excess of unnecessary repetitions as well as irrelevant, idiosyncratic acts (additions) compared to normal activity. A question that still remains is whether these well-known repetitions and additions are manifested in behaviors unrelated to the OCD rituals. Our objectives were to: (1) assess whether OCD-related repetitions and additions as found in previous studies also affect the patients' activity of filling out questionnaires and (2) evaluate the specificity of these behaviors to OCD as opposed to other anxiety disorders and healthy controls. SAMPLING AND METHODS: Several standardized disorder-specific self-report questionnaires were used in order to assess the patient's psychopathologies. The style of filling-out these questionnaires by OCD and non-OCD anxiety outpatients and normal controls was analyzed. Four categories were used: omissions, repetitions, corrections, and additions. RESULTS: The OCD group scored significantly higher on the number of additions as compared with both the anxiety group and the nonclinical group, and significantly higher on the number of corrections and repetitions as compared with the nonclinical group. CONCLUSIONS: The hallmarks of OCD, repetitions and additions, are manifested not only in the patient's rituals and thoughts, but in apparently "neutral" tasks that do not a priori involve the intrusive thoughts, urges, and images typical of obsessive-compulsive behavior. Additions seem to be more specific to OCD than repetitions. These two executive faults impede routine functionality of OCD patients in tasks related and unrelated to their rituals. Our study delineates simple, observable behavioral characteristics that distinguish between OCD and non-OCD anxiety patients as well as healthy individuals. These symptomatic behaviors may offer a clue to personality traits or deficits in executive functions that possibly play a part in the pathophysiology of OCD. Our results are an additional indication that nonfunctionality in obsessive-compulsive behavior deserves full attention for a better understanding of the psychopathological mechanisms of OCD.

Comparison of medical treatment of patients with schizophrenia in general practitioners' clinics versus mental health clinics: A cohort study.

OBJECTIVES: Individuals with schizophrenia have more cardiometabolic comorbidities than the general population, live about twenty years less and consume more medical services. They are treated at general practitioners' clinics (GPCs) or at mental health clinics (MHCs). In this cohort study we investigated the association between patients' main treatment setting, cardiometabolic comorbidities and medical services utilization. METHODS: Demographics, healthcare services utilization, cardiometabolic comorbidities and medication prescriptions of patients with schizophrenia were retrieved from an electronic database for the period 1.1.2011 to 31.12.2012 and compared between patients treated mostly in MHCs (N = 260) and those treated mostly in GPCs (N = 115). RESULTS: GPC patients tended to be older (mean age 39.8 ± 13.7 vs. 34.6 ± 12.3 yrs., p < 0.0001), of lower socioeconomic status (42.6% vs 24.6%, p = 0.001) and have more cardiometabolic diagnoses (hypertension: 19.1% vs 10.8%, diabetes mellitus: 25.2% vs 17.0%, p < 0.05) than MHC patients. The former received more cardiometabolic disorder medications and utilized more secondary and tertiary medical services. Charlson Comorbidity Index (CCI) was higher in the GPC group than in the MHC group (1.8 ± 1.9 vs.1.2 ± 1. 6, p < 0.0001). A multivariate binary logistic regression analysis, adjusted for age, sex, SES and CCI found lower adjusted odds ratio for the MHC group versus the GPC group, of visiting an EMD, a specialist or to be hospitalized. CONCLUSIONS: The current study highlights the critical importance of integrating GPCs and MHCs, thus offering patients combined physical and mental care at a single location. More studies on the potential benefits of such integration to patients' health are warranted.

Adherence of patients with schizophrenia to hypothyroidism treatment.

Adherence to prescription medications is critical for both remission from schizophrenia and control of physical comorbidities. While schizophrenia with comorbid hypothyroidism is common, there is little research on adherence to hypothyroidism treatment in this population. The current study used a retrospective, matched case-control design. The cohort included 1,252 patients diagnosed with schizophrenia according to ICD-10 and 3,756 controls matched for gender, age, socioeconomic status and ethnicity without diagnosis of schizophrenia. All data were retrieved from the electronic medical database of a large health maintenance organization. Retrieved data included demographics, thyroid functionality test results and prescribed medications. Measures of adherence to therapy were used for analyses as were data from follow-ups of patients with hypothyroidism. A diagnosis of hypothyroidism was found in 299 patients, 115 of whom were also diagnosed with schizophrenia. The 184 without schizophrenia constituted the control group. No statistically significant differences were found between the two groups regarding prescriptions for L-thyroxin and TSH levels and number of TSH tests. Adherence of patients with schizophrenia to hypothyroidism treatment was found to be as good as that of individuals without a schizophrenia diagnosis.

Gestational hemodilution as a putative risk factor for postpartum depression: A large-scale nationwide longitudinal cohort study.

BACKGROUND: While anemia during pregnancy has been linked to increased postpartum depression (PPD) risk, longitudinal studies on the association between gestational hemodilution, represented by decreased hematocrit (Hct) during the transition from the 1st to 2nd trimester, and PPD risk, are scarce. The current study aimed to investigate this association in a nationwide cohort over the perinatal period. METHODS: This retrospective cohort study included 104,715 women who gave birth between January 2008 and December 2015. The cohort was followed up for new-onset PPD during the year post birth and gestational hemodilution was assessed by the change in Hct levels (Δ: 2nd-1st trimester). The cohort was divided into three hemodilution groupings: maximal and minimal 10 % of mothers and intermediate 80 %. Multivariable regression analyses were performed to estimate the association between gestational hemodilution and PPD, adjusting for confounders. RESULTS: Among the full cohort, 2.2 % (n = 2263) met the definition of new-onset PPD. Mothers with greater hemodilution had higher rates of PPD: 2.7 % (n = 269) in the maximal hemodilution group, 2.1 % (n = 1783) in the intermediate and 1.9 % (n = 211) in the minimal hemodilution group (p < 0.001). The maximal hemodilution group had higher rates of pre-gestational psychiatric disorders (p < 0.001) and higher adjusted risk for PPD [OR = 1.18, 95 % CI (1.04, 1.35)]. LIMITATIONS: Data on iron levels and supplementation were unavailable, thus it could not be adjusted for in the analysis. CONCLUSIONS: Women in the top 10th percentile of gestational hemodilution may be at risk for PPD, justifying monitoring of gestational Hct as a biomarker for PPD.

Attenuated Access to Emotions in Obsessive-Compulsive Disorder.

The Seeking Proxies for Internal States (SPIS) model of obsessive-compulsive disorder (OCD) posits that OCD is associated with attenuated access to internal states. Here we explored the implications of this model in the realm of emotions. Participants with OCD, anxiety disorders, and nonclinical control participants completed the Mayer-Salovey-Caruso Emotional Intelligence Test (MSCEIT), assessing two domains of emotional intelligence: Experiential emotional intelligence (EI), reflecting the ability to perceive and feel emotions accurately, and Strategic EI, reflecting the ability to understand and manage emotions correctly. As only Experiential EI requires accurate perception of one's emotions for adequate performance, we predicted an interaction between group and EI area. Specifically, we predicted that compared to both anxiety disorders and healthy control participants, OCD participants would show a larger deficit in Experiential area of the MSCEIT relative to the Strategic area. Results were fully in line with this prediction. Moreover, supporting the specificity of the hypothesized deficit to OCD, participants with anxiety disorders did not differ from nonclinical control participants in their performance, and findings were not attributable to anxiety or depression levels. These results replicate and extend previous findings obtained with analogue samples and suggest that OCD is associated with attenuated access to emotional states, which may be partially compensated for by reliance on semantic knowledge of emotion.

Comorbid personality disorders in manic bipolar I disorder patients is associated with increased use of long-acting injectable antipsychotic treatment and higher rates of rehospitalization.

Personality disorder comorbidity is considered a poor prognostic factor among bipolar disorder patients. However, an evidence-based pharmacological treatment for this sub-population is lacking, and only few studies investigated the impact of personality disorder on bipolar disorder-I course. Here, we studied the effect of comorbid personality disorder on the administrated psychopharmacotherapy and rehospitalization risk among manic bipolar disorder-I patients. A sample of 340 patients with bipolar disorder-I, who were hospitalized with acute manic episode between 2005 and 2013, were retrospectively followed for a mean duration of 1129 days. Drug treatment at discharge and rehospitalization rates during follow-up time were compared between bipolar disorder-I patients with (n = 55) or without (n = 285) personality disorder comorbidity. Multivariate survival analyses adjusted for covariates were conducted. During the study period, 39.4% of bipolar disorder-I patients were rehospitalized due to a mood episode. Comorbid personality disorder was significantly associated with higher rates of long-acting injectable antipsychotics administration at discharge from hospitalization (adjusted odds ratio 2.66, 95% confidence interval: 1.19-5.94, P = 0.017). Comorbid personality disorder significantly increased the adjusted risk of rehospitalization due to a mood episode (hazard ratio = 2.04, 95% confidence interval: 1.29-3.23, P = 0.002). In conclusion, comorbid personality disorder in manic bipolar disorder-I patients is associated with increased use of long-acting injectable antipsychotics and higher rates of rehospitalization.

Thyroid function assessment before and after diagnosis of schizophrenia: A community-based study.

Alterations in thyroid hormone levels may affect brain and mental disorders. Conversely, schizophrenia and its antipsychotic treatments can affect thyroid hormone levels. However, data on thyroid hormone levels during the course of schizophrenia disorder are scant. The aim of the study was to assess the rate of thyroid hormone disorders in outpatients before and after diagnosis of schizophrenia. A retrospective matched-control design was used. The cohort included 1252 patients suffering from ICD-10 schizophrenia, and 3756 control subjects matched for gender, age, socioeconomic status, and origin. All were identified from the database of a large health management organization. The pertinent clinical data were collected from the electronic medical records. There was no significant between-group difference in the distribution of thyroid-stimulating hormone levels. Before diagnosis, both groups had a similar rate of hypothyroidism. After diagnosis of schizophrenia and initiation of antipsychotic treatment, the rate of hypothyroidism was significantly higher in the patient group. It remained significantly higher after exclusion of patients receiving lithium. The increased rate of hypothyroidism in patients with schizophrenia after, but not before, the diagnosis of schizophrenia suggests that antipsychotic medications may affect thyroid hormone levels. Screening for thyroid disorders is warranted in patients with schizophrenia under antipsychotic treatment.

Adjunctive antidepressants in bipolar depression: A cohort study of six- and twelve-months rehospitalization rates.

Although antidepressants (ADs) are widely used in bipolar depression, there is weak evidence for their effectiveness and safety in this condition. Furthermore, there is a paucity of studies on the risk-benefit ratio of AD maintenance treatment in bipolar disorder (BD). We compared rehospitalization rates of patients with BD-I depressive episode who were discharged with mood stabilizers (MSs) and/or atypical antipsychotics (AAPs) with or without adjunctive AD. Ninety-eight patients with BD-I who were hospitalized with a depressive episode between 2005 and 2013 were retrospectively followed for 6-months and 1-year rehospitalization rates, as well as time to rehospitalization, according to treatment at discharge: MSs and/or AAPs with or without AD. Multivariable survival models adjusted for covariates known to influence rehospitalization were conducted. Six-months and 1-year rehospitalization rates were significantly lower in the adjunctive-AD treatment group compared to the no-AD group (9.2% vs. 36.4%, P = .001, power = 0.87 and 12.3% vs. 42.4%, P = .001, power = 0.89, respectively). Time to rehospitalization within 6-months and 1-year was significantly longer in the adjunctive-AD treatment group (169.9 vs 141 days, P = .001 and 335.6 vs 252.3 days, P = .001, respectively). Adjunctive-AD treatment at discharge reduced significantly the adjusted risk of rehospitalization within 6-months (HR = 0.081, 95% CI: 0.016-0.412, P = 0.002) and 1-year (HR = 0.149, 95% CI: 0.041-0.536, P = 0.004). Moreover, adjunctive-AD treatment did not increase rehospitalization rates of manic episode. In conclusion, adjunctive-AD therapy to MS/AAP at discharge from BD-I depressive episode hospitalization is associated with a lower rate of and a longer time to rehospitalization during a 1-year follow up period.

Mortality, morbidity and medical resources utilization of patients with schizophrenia: A case-control community-based study.

Patients with schizophrenia have higher level of mortality and physical comorbidity compared to control population. However the association to primary-, secondary- and tertiary-medical resources utilization is not clear. We used a retrospective community-based cohort of patients with schizophrenia (n=1389; age 37.53 years, 64.3% males) and, age-, gender-, and socioeconomic status-matched controls (n=4095; age 37.34 years; 64.3% males) who were followed-up for nine years. Mortality rate of patients was almost twice as high as that of matched controls (7% versus 3.8%). Diagnoses of ischemic heart disease and hypertension were more prevalent among controls than patients (8.2% versus 5%, and 21.6% versus 15.8%, respectively). Tertiary medical resources utilization was higher among patients with schizophrenia than control population (mean hospital admissions per year: 0.2 versus 0.12, emergency department visits: 0.48 versus 0.36). Patients that died were more likely to have cardiovascular disease, to be admitted to general hospital and to spend more days in hospital than patients that did not die. There is a discrepancy between lower rates of cardiovascular disease diagnoses but higher rates of mortality and tertiary medical resources utilization among patients with schizophrenia when compared to control population. This may stem from an under-diagnosis and, eventually, under-treatment of these patients.

Adjustment disorder: a review of diagnostic pitfalls.

Adjustment disorder is a common diagnosis in psychiatric settings and carries a significant rate of morbidity and mortality. However, both current and previous diagnostic criteria are vague and lead to many difficulties in terms of validity and reliability. This review is based on a thorough literature search and a systematic evaluation of the empiric and theoretic data. The various pitfalls inherent in the process of diagnosing this disorder are discussed in light of the diagnostic criteria for the disorder.

QT dispersion in patients with social phobia.

BACKGROUND: QT dispersion (QTd) is the maximal interlead difference in QT interval on the surface 12-lead electrocardiogram (ECG). An increase in QTd is found in various cardiac diseases and reflects cardiac autonomic imbalance. It has recently been associated with increased anxiety levels, thereby predisposing affected individuals to fatal heart disease. This is the first study to assess QTd in social phobia, as a marker of anxiety-induced cardiac dysregulation. METHODS: QTd and rate-corrected QTd were measured in 16 physically healthy and non-depressed outpatients with long-term (mean 28+/-12.2 years; age 37.9+/-9.6 years) social phobia (SP) and in 15 physically and mentally healthy age- and gender-matched controls. The Liebowitz Social Anxiety Scale (LSAS) was scored concomitantly. The intra- and inter-observer reproducibilities of QTd were highly correlated (r=0.96, P<0.001; r=0.74, P=0.002, respectively). RESULTS: QTd and rate-corrected QTd were significantly higher in the patients with SP compared to the controls (70+/-21 versus 43+/-10 ms, P<0.001 and 75+/-23 versus 46+/-10 ms, P<0.001, respectively), and highly correlated with the two LSAS subscores. CONCLUSIONS: Prolonged SP is associated with an increase in QTd. This association may result from prolonged anxiety and, in turn, a decrease in vagal modulation and/or increase in sympathetic modulation. Further large-scale epidemiological studies are needed to determine if increased QTd can serve as a trait/state marker, and if it is a risk factor for sudden cardiac death in patients with SP.

Late potentials in the signal-averaged electrocardiogram in schizophrenia patients maintained on antipsychotic agents: a preliminary naturalistic study.

In the present, preliminary, naturalistic study, cardiac ventricular late potentials (LPs), were measured in 33 physically healthy schizophrenia patients (13 - females and 26 - males, age - 45.5+/-8.8years) maintained on typical and atypical antipsychotic agents. These LPs represent delayed ventricular activation that might predispose to fatal ventricular arrhythmias and sudden cardiac death (SCD) in cardiac patients. Sixteen of the 33 patients ( approximately 48%) were found to be positive for LPs (compared to 3.7-6% in the general population). No association was found with any of the following: drug type, anti-cholinergic burden, daily dose of antipsychotic agents, age, gender, disease duration, QT(c) interval and QT dispersion. Further large-scale longitudinal prospective studies are warranted to substantiate our findings and to clarify their impact on the excess cardiac morbidity and mortality in schizophrenia patients.

Psychometric properties and three proposed subscales of a self-report version of the Liebowitz Social Anxiety Scale translated into Hebrew.

We investigated the overall test-retest reliability and other psychometric properties of a self-report version of the Liebowitz Social Anxiety Scale (LSAS) translated into Hebrew. We also evaluated the utility of three new subscales that were identified by nonparametric analysis (multidimensional scaling; MDS). Two hundred and seven patients who sought treatment for social anxiety or panic disorder were evaluated. All patients completed the self-administered version of the LSAS. A subsample completed the LSAS a second time prior to the beginning of treatment. The results indicate that the self-report format of the LSAS translated into Hebrew demonstrates high test-retest reliability, internal consistency, and discriminant validity. Additionally, some evidence for convergent and divergent validity was noted, and treatment sensitivity was high. MDS analysis followed by the investigation of common underlying facets for items related in two-dimensional space identified three subgroups: 1) the Group Performance/Interaction ("Group") subscale that consists of group performance and group interaction items; 2) the Dyadic Interaction ("Dyadic") subscale that consists of Dyadic interaction items; and 3) the Public Activities ("Public") subscale that consists of individual activities carried out in public. The three new subscales identified by MDS appear to provide clinically relevant information that relates to both demographic and treatment outcome variables and warrant further study.