[PUBLIC EXPENDITURE ON MENTAL HEALTH IN ISRAEL: CALCULATION, ANALYSIS AND INTERNATIONAL COMPARISON].

INTRODUCTION: This is the first health economics study to calculate and analyze public expenditure on mental health in Israel from 2019 through 2021. Financing of the NIS 4 billion expenses is divided equally between the health funds and direct financing from the state budget.

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.

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.

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.

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.

Synthesis and preliminary biological evaluation of gabactyzine, a benactyzine-GABA mutual prodrug, as an organophosphate antidote.

Organophosphates (OPs) are inhibitors of acetylcholinesterase and have deleterious effects on the central nervous system. Clinical manifestations of OP poisoning include convulsions, which represent an underlying toxic neuro-pathological process, leading to permanent neuronal damage. This neurotoxicity is mediated through the cholinergic, GABAergic and glutamatergic (NMDA) systems. Pharmacological interventions in OP poisoning are designed to mitigate these specific neuro-pathological pathways, using anticholinergic drugs and GABAergic agents. Benactyzine is a combined anticholinergic, anti-NMDA compound. Based on previous development of novel GABA derivatives (such as prodrugs based on perphenazine for the treatment of schizophrenia and nortriptyline against neuropathic pain), we describe the synthesis and preliminary testing of a mutual prodrug ester of benactyzine and GABA. It is assumed that once the ester crosses the blood-brain-barrier it will undergo hydrolysis, releasing benactyzine and GABA, which are expected to act synergistically. The combined release of both compounds in the brain offers several advantages over the current OP poisoning treatment protocol: improved efficacy and safety profile (where the inhibitory properties of GABA are expected to counteract the anticholinergic cognitive adverse effects of benactyzine) and enhanced chemical stability compared to benactyzine alone. We present here preliminary results of animal studies, showing promising results with early gabactyzine administration.

Clozapine blood level assessment using a point-of-care device: feasibility and reliability.

Background: Therapeutic drug monitoring (TDM) is useful to assess clozapine adherence and optimize treatment. However, analysis of venous blood levels by liquid chromatography tandem mass spectrometry (LC-MS/MS) is often logistically complicated and process time is prolonged. Objective: To assess the feasibility and reliability of a new point-of-care device, (MyCare™ Insite), using capillary blood for clozapine therapeutic monitoring. Methods: Matched venous and capillary blood samples were collected from patients treated with clozapine on a stable dose. Samples were analyzed by LC-MS/MS and MyCare Insite Clozapine Test. Clozapine plasma levels were compared between methods using linear regression model. Both patients and treatment team completed questionnaires about the feasibility of blood sampling. Results: Of the total sample (44 patients, 61% males, mean age 43 ± 12 years), mean daily clozapine dose was 293 ± 134 mg/day. Linear regression model demonstrated high correlation with R 2 = 0.83 (p < 0.0001) and mean difference of 26 ± 162 ng/ml. More than 60% of the patients found the clozapine TDM to be important. Most of the participants (58%) favored the capillary sampling and 11% claimed that testing method would affect their adherence to TDM. Moreover, a larger portion (72%) strongly preferred to be tested at the office rather than at the lab. Conclusions: The point-of-care device offers an accessible and satisfactory measurement of clozapine blood levels. Both patients and healthcare providers reported preference for capillary sampling as well as for the in-office TDM procedure. The immediate results provided by the device can facilitate rapid and informed clinical decisions and therefore improve clozapine treatment outcomes.

New approaches to antipsychotic medication adherence - safety, tolerability and acceptability.

INTRODUCTION: Antipsychotic pharmacotherapy is considered a first-line treatment in schizophrenia-related disorders and is associated with favorable prognosis and lower mortality rates. However, low adherence rates present a major clinical challenge. In this paper, we will review contemporary approaches to improve adherence to antipsychotic treatment, considering their mechanism of action, safety, tolerability and acceptability. AREAS COVERED: Novel pharmacological delivery methods included different routes of administration of registered medications (such as intramuscular clozapine preparation and transdermal asenapine), modifications of existing compounds (such as 3-monthly injectable formulation of paliperidone palmitate), and increased interest in oral long-acting medication formulations (such as with penfluridol). In addition, we reviewed innovative technology to monitor adherence, based on the use of electronic digital medicine systems and ingestible sensors. EXPERT OPINION: All of these diverse approaches were clinically relevant in enhancing treatment adherence and found to be safe and tolerable. The place of each approach is predicated on a personalized approach in each patient, and future research could usefully use large comparative studies to establish robust treatment guidelines. The implementation of new and varied approaches to antipsychotic treatment adherence is welcomed and have the potential to make a significant impact on morbidity in this often difficult-to-treat population.

Predictive value of cardiometabolic biomarkers and depressive symptoms for symptom severity and quality of life in patients with psychotic disorders.

BACKGROUND: Patients with psychotic disorders show higher rates of the metabolic syndrome (MS) between the cluster of severe mental illnesses. Depressive symptoms can worsen outcomes of individuals with psychotic disorders. However, research on the association between MS and depression in psychotic disorders and their relevance to outcomes is lacking. METHODS: We investigated the association between depression and cardiometabolic biomarkers in psychotic disorders and the predictive value of depressive symptoms on psychopathological severity and quality of life (QoL). 406 patients with psychotic disorders were recruited as part of the Improving Physical Health and Reducing Substance Use in Severe Mental Illness randomised controlled trial. Depression, psychotic symptoms, QoL, waist circumference, triglycerides, high-density lipoprotein cholesterol (HDL-C), blood pressure, and fasting glucose of patients were assessed at baseline and 12 months. Sensitivity analyses were conducted to test the effect of treatment. RESULTS: More severe baseline symptoms of depression significantly predicted worse 12-month psychotic symptoms and lower mental health related QoL at 12 months. These associations held after controlling for alcohol use, gender, ethnicity, education, and mental health related QoL Baseline. Depressive symptoms also correlated with waist circumference at both baseline and 12 months, after controlling for multiple testing. CONCLUSION: Individuals with psychotic disorders experiencing more severe depressive symptoms are more likely to have larger waist circumference contemporaneously and 12 months later, as well as more severe psychotic symptoms and worse QoL at follow-up. This highlights the need for evaluation of strategies to address depression in the management of psychotic disorders.

Effect of Vitamin D Supplementation on Outcomes in People With Early Psychosis: The DFEND Randomized Clinical Trial.

Importance: People with psychotic disorders have an increased risk of vitamin D deficiency, which is evident during first-episode psychosis (FEP) and associated with unfavorable mental and physical health outcomes. Objective: To examine whether vitamin D supplementation contributes to improved clinical outcomes in FEP. Design, Setting, and Participants: This multisite, double-blind, placebo-controlled, parallel-group randomized clinical trial from the UK examined adults 18 to 65 years of age within 3 years of a first presentation with a functional psychotic disorder who had no contraindication to vitamin D supplementation. A total of 2136 patients were assessed for eligibility, 835 were approached, 686 declined participation or were excluded, 149 were randomized, and 104 were followed up at 6 months. The study recruited participants from January 19, 2016, to June 14, 2019, with the final follow-up (after the last dose) completed on December 20, 2019. Interventions: Monthly augmentation with 120 000 IU of cholecalciferol or placebo. Main Outcomes and Measures: The primary outcome measure was total Positive and Negative Syndrome Scale (PANSS) score at 6 months. Secondary outcomes included total PANSS score at 3 months; PANSS positive, negative, and general psychopathology subscale scores at 3 and 6 months; Global Assessment of Function scores (for symptoms and disability); Calgary Depression Scale score, waist circumference, body mass index, and glycated hemoglobin, total cholesterol, C-reactive protein, and vitamin D concentrations at 6 months; and a planned sensitivity analysis in those with insufficient vitamin D levels at baseline. Results: A total of 149 participants (mean [SD] age, 28.1 (8.5) years; 89 [59.7%] male; 65 [43.6%] Black or of other minoritized racial and ethnic group; 84 [56.4%] White [British, Irish, or of other White ethnicity]) were randomized. No differences were observed in the intention-to-treat analysis in the primary outcome, total PANSS score at 6 months (mean difference, 3.57; 95% CI, -1.11 to 8.25; P = .13), or the secondary outcomes at 3 and 6 months (PANSS positive subscore: mean difference, -0.98; 95% CI, -2.23 to 0.27 at 3 months; mean difference, 0.68; 95% CI, -0.69 to 1.99 at 6 months; PANSS negative subscore: mean difference, 0.68; 95% CI, -1.39 to 2.76 at 3 months; mean difference, 1.56; 95% CI, -0.31 to 3.44 at 6 months; and general psychopathology subscore: mean difference, -2.09; 95% CI, -4.36 to 0.18 at 3 months; mean difference, 1.31; 95% CI, -1.42 to 4.05 at 6 months). There also were no significant differences in the Global Assessment of Function symptom score (mean difference, 0.02; 95% CI, -4.60 to 4.94); Global Assessment of Function disability score (mean difference, -0.01; 95% CI, -5.25 to 5.23), or Calgary Depression Scale score (mean difference, -0.39; 95% CI, -2.05 to 1.26) at 6 months. Vitamin D levels were very low in the study group, especially in Black participants and those who identified as another minoritized racial and ethnic group, 57 of 61 (93.4%) of whom had insufficient vitamin D. The treatment was safe and led to a significant increase in 25-hydroxyvitamin D concentrations. Conclusions and Relevance: In this randomized clinical trial, no association was found between vitamin D supplementation and mental health or metabolic outcomes at 6 months. Because so few patients with FEP were vitamin D replete, the results of this study suggest that this group would benefit from active consideration in future population health strategies. Trial Registration: isrctn.org Identifier: ISRCTN12424842.

Brain Motor Region Diffusion Tensor Imaging in Patients with Catatonic Schizophrenia: A Case-Control Study.

BACKGROUND: Only a small proportion of schizophrenia patients present with catatonic symptoms. Imaging studies suggest that brain motor circuits are involved in the underlying pathology of catatonia. However, data about diffusivity dysregulation of these circuits in catatonic schizophrenia are scarce. OBJECTIVES: To assess the involvement of brain motor circuits in schizophrenia patients with catatonia. METHODS: Diffusion tensor imaging (DTI) was used to measure white matter signals in selected brain regions linked to motor circuits. Relevant DTI data of seven catatonic schizophrenia patients were compared to those of seven non-catatonic schizophrenia patients, matched for sex, age, and education level. RESULTS: Significantly elevated fractional anisotropy values were found in the splenium of the corpus callosum, the right peduncle of the cerebellum, and the right internal capsule of the schizophrenia patients with catatonia compared to those without catatonia. This finding showed altered diffusivity in selected motor-related brain areas. CONCLUSIONS: Catatonic schizophrenia is associated with dysregulation of the connectivity in specific motoric brain regions and corresponding circuits. Future DTI studies are needed to address the neural correlates of motor abnormalities in schizophrenia-related catatonia during the acute and remitted state of the illness to identify the specific pathophysiology of this disorder.

Outcomes in treatment-resistant schizophrenia: symptoms, function and clozapine plasma concentrations.

BACKGROUND: Clozapine is the only medication licenced for treating patients with treatment-refractory schizophrenia. However, there are no evidence-based guidelines as to the optimal plasma level of clozapine to aim for, and their association with clinical and functional outcome. OBJECTIVE: We assessed the relationship between clinical and functional outcome measures and blood concentrations of clozapine among patients with treatment-refractory psychosis. METHODS: Data were reviewed in 82 patients with treatment-refractory psychosis admitted to a specialised tertiary-level service and treated with clozapine. Analysis focussed on the relationship between clozapine and norclozapine plasma concentrations and the patient's clinical symptoms and functional status. RESULTS: Clinical symptom improvement was positively correlated with norclozapine plasma concentrations and inversely correlated with clozapine to norclozapine plasma concentrations ratio. Clozapine concentrations showed a bimodal association with clinical improvement (peaks around 350 and 660 ng/ml). Clinical symptom improvement correlated with functional outcomes, although there was no significant correlation between the latter and clozapine or norclozapine plasma concentrations. CONCLUSION: Clozapine treatment was associated with optimal clinical improvement at two different peak plasma concentrations around 350 and 650 ng/ml. Clinical improvement was associated with functional outcome; however, functionality was not directly associated with clozapine concentrations. A subset of patients may require higher clozapine plasma concentrations to achieve clinical improvement.

Trends of new-onset psychosis or mania in psychiatric emergency departments during the COVID19 pandemic: a longitudinal comparative study.

COVID19 infection was associated with possible psychiatric manifestations, including psychosis and mania. In addition, psychiatric disorders might be triggered by severe psychological reactions to the pandemic or the measures taken to contain it. This study aimed to assess the trends of new-onset psychosis/mania during the pandemic timeline. Psychiatric emergency department records during January-July 2019 and 2020 of two regional mental health centers were manually examined. Cases of new-onset psychosis or mania were found in 326 out of 5161 records examined. The ratio of these cases increased by 45.5% in 2020 compared to 2019 (189 out of 2367, 137 out of 2479, respectively, p = 0.001). The peak increase was in April 2020 (9.4% vs. 4.7%, p = 0.015). There was no association between the rise of new-onset psychotic or manic episodes and national incidence of COVID19 cases, as observed during Israel 2nd wave. PCR tests were negative, except a single case. In this study, an increase in new-onset psychosis/mania was identified during the initial phase of the pandemic. Though causality could not be directly inferred, lack of infection symptoms, negative PCR testing and temporal distribution incongruent with COVID19 caseload did not support a direct effect of SARS-CoV-2. Alternative explanations are discussed, such as psychological reaction to stress and preventive measures, as well as case-shifting between different mental health settings.

The association of medical resource utilization with physical morbidity and premature mortality among patients with schizophrenia: An historical prospective population cohort study.

BACKGROUND: Schizophrenia patients have shorter life expectancy often owing to preventable physical illnesses and sub-optimal utilization of medical services. However, the association between service-utilization and mortality has not been explored. AIM: To assess whether medical service-utilization moderates the association between physical morbidity and premature mortality in a nation-wide cohort. METHODS: A population representative database of the largest health provider in Israel was analyzed. All electronic health records of patients with schizophrenia diagnosis (ICD code F.20) (n = 24,679) were followed-up between 2012 and 2015, and compared to the general population (n = 2,232,804), in terms of metabolic and cardiovascular morbidity, all-cause mortality, primary medical and specialist health service-utilization and general hospitalizations. RESULTS: Schizophrenia was associated with increased mortality risk (adjusted hazard ratio (aHR) = 3.52, 95%CI 3.35-3.72). Most deaths were related to physical illnesses. Metabolic syndrome components, except chronic hypertension, were more prevalent among patients. They were referred more frequently to primary and less to secondary services (aHR = 1.05, 95%CI 1.04-1.06, aHR = 0.95, 95%CI 0.94-0.97, respectively), with higher hospitalization rates (0.23 ± 0.90 vs 0.10 ± 0.50 per year), and longer mean duration of hospitalization (2.02 ± 10.24 vs 0.68 ± 5.51 days, P < 0.001). More contacts with primary care physicians or specialists positively moderated the association between mortality and metabolic disturbances in patients with schizophrenia; more contacts were associated with better outcomes. CONCLUSIONS: An association between premature mortality and metabolic syndrome was found among schizophrenia patients while utilization of primary/secondary medical services moderated the lethal effects of metabolic dysregulation. Increased integrative primary care and a national monitoring system are warranted to reduce mortality rate in this population.

Association between Adherence to SSRI Treatment and Mortality among Individuals with Metabolic Syndrome Components.

INTRODUCTION: Depression and anxiety have been associated with type 2 diabetes mellitus and metabolic syndrome, major causes of cardiovascular morbidity and mortality. The effect of antidepressants in this association is unknown. This study aimed to examine the association between adherence to selective serotonin receptor inhibitors (SSRIs) and all-cause mortality among individuals with metabolic syndrome components (hypertension, obesity, and diabetes mellitus). METHODS: Data on 201 777 patients who were prescribed SSRIs during the years 2008-2011 were analyzed retrospectively. Adherence was measured using prescription purchase records. The moderating effect of SSRI and statin adherence on the association between metabolic syndrome load and mortality hazard risk (HR) during the study period were analyzed. The Cox-proportional hazard model adjusted to background variables was used to this end. RESULTS: During the study period, the maximal metabolic load was associated with mortality HR=1.89 (95% CI: 1.79-2) compared to participants without metabolic risk factors. A slight reduction in mortality HR was demonstrated among those with low and moderate SSRI adherence rates. Adherence to statins was negatively associated with the risk of mortality across all levels of adherence. A significant association (r=0.214, p<0.01) was found between adherence to statins and adherence to SSRIs, with higher rates of adherence to statins across all metabolic load categories. DISCUSSION: While a high metabolic load is associated with a higher risk of mortality, adherence to SSRIs only partially moderated the risk of mortality, in contrast to the protective effect of statins. Adherence differences to statins and SSRIs among individuals prescribed both medications merit further investigation.

[PREVALENCE OF TOBACCO SMOKING AMONG MENTAL HEALTH INPATIENTS IN ISRAEL].

INTRODUCTION: Tobacco smoking is the worldwide leading preventable cause of morbidity [1]. The prevalence of current smoking among individuals with mental illnesses is more than twice as that of the general population [2]. Despite it being a primary cause of morbidity and mortality in Israel too, there is little information and research on the features of smoking among people with mental illnesses in Israel. OBJECTIVES: To present an up-to-date estimation of the prevalence of smoking among hospitalized patients with mental illness in Israel and to compare the prevalence of comorbidities among smokers and non-smokers in this population. METHODS: Analyzing data obtained from an electronic medical-records database, consisting of 4646 patients with mental illness, aged 18-90 years, who were hospitalized at Geha Mental Health Center during 2005-2013. RESULTS: The smoking rate among hospitalized patients with mental illness was significantly higher than the general population (51.3% versus 19.7%, respectively). The smoking rate among male hospitalized patients with mental illness was higher than that of the females (58.2% versus 42.7%, respectively), however, the difference between men and women is smaller compared to this difference in the general population. Smoking rates were highest among those with personality disorder (65.1%), bipolar disorder (58.8%) and schizophrenia (53.81%). The prevalence of comorbid substance use (alcohol or drug abuse) among hospitalized patients with mental illness was found to be higher in the smokers group than in the non-smokers group (37.4% versus 4.6%, respectively, p<0.0001). CONCLUSIONS: The prevalence of smoking among hospitalized patients with mental illness in Israel is 2.74 times that of the general population in 2013, in line with the reported worldwide rate. In addition, among hospitalized patients with mental illness the prevalence of comorbid substance use (alcohol or drug abuse) was higher among the smokers than among the non-smokers.

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.

Augmentation of clozapine with ECT: a retrospective case analysis.

OBJECTIVE: We sought to assess the effectiveness of clozapine augmentation with Electroconvulsive therapy (ECT) (C+ECT) in patients with clozapine-resistant schizophrenia. METHODS: We conducted a retrospective review of electronic health records to identify patients treated with C+ECT. We determined the response to C+ECT and the rate of rehospitalisation over the year following treatment with C+ECT. RESULTS: Forty-two patients were treated with C+ECT over a 10-year period. The mean age of the patients at initiation of ECT was 46.3 (SD = 8.2) years (range 27-62 years). The mean number of ECTs given was 10.6 (SD = 5.3) (range 3-25) with the majority receiving twice weekly ECT. Seventy-six per cent of patients (n = 32) showed a Clinical Global Impression-Improvement (CGI-I) score of ≤3 (at least minimally improved) following C+ECT. The mean number of ECT treatments was 10.6 (SD = 5.3) (range 3-25) with the majority receiving twice weekly ECT. Sixty-four per cent of patients experienced no adverse events. Response to C+ECT was not associated with gender, age, duration of illness or duration of clozapine treatment. Seventy-five per cent of responders remained out of hospital over the course of 1-year follow-up, while 70% of those with no response to C+ECT were not admitted to hospital. Three patients received maintenance ECT, one of whom was rehospitalised. CONCLUSION: This study lends support to emerging evidence for the effectiveness of C+ECT in clozapine-resistant schizophrenia. These results are consistent with the results of a meta-analysis and the only randomised controlled trial (RCT) of this intervention. Further RCTs are required before this treatment can be confidently recommended.

Metabolic predictors for mortality among patients treated with long-term clozapine - A longitudinal study.

Clozapine is the only antipsychotic compound indicated for refractory-schizophrenia. However, it is associated with emergent metabolic dysregulation and cardiovascular risk which may lead to mortality. In this study we aimed to explore predictors for mortality in a large cohort of schizophrenia patients treated with long-term clozapine, using the electronic medical records of the largest health care provider in Israel. Among 27,929 patients diagnosed with schizophrenia, 1817 were prescribed clozapine during the years 2012-2014. We compared patients who survived (n=1705) and patients who died (n=112) during the 3-year follow-up period. Socio-demographic background, cardiovascular morbidity, medication prescriptions and health-care utilization were compared between groups. Cox proportional hazard models were used to assess the association of variables with survival. Chronic hypertension was found to be the only metabolic factor associated with significant hazard ratio (HR) for mortality (HR: 1.55 95% CI: 1.03-2.34). Moreover, those who died had more prevalent ischemic heart disease (14% vs 3%, p<0.005) as well as more frequent hospitalizations (0.01±0.02 vs 0.11±0.18 average per month, p<0.005), for longer periods (2.22±9.87 vs 20.38±33.76 days per month, p<0.005). Among those who died, less patients received prescriptions of statins for hyperlipidemia (13.7% vs. 52.9% in survivors, p<0.005) and hypoglycemics for diabetes mellitus (16.3% vs. 67.1% in survivors, p<0.005). Inadequate treatment of metabolic syndrome, under chronic clozapine treatment, was found to be an independent predictor for mortality. Adequate rigorous regimen for diagnosis and treatment of metabolic risk factors, especially hyperlipidemia and diabetes mellitus, might lower complications rate and prolong life expectancy among this population.

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.