[THE USE OF AMBULATORY PSYCHIATRIC SERVICES AMONG THE ISRAELI POPULATION FOLLOWING THE OCTOBER 7 TERROR ATTACKS AND IRON SWORDS WAR].

BACKGROUND: On October 7, 2023, operation "Iron Swords" erupted following a barbaric terror attack, resulting in over 1,200 casualties, with more than 250 individuals, abducted. The aftermath of this slaughter led to the evacuation of hundreds of thousands from their homes in both the south and north of Israel. This situation triggered an unprecedented surge in the request for mental health support as reported by health funds and helplines. Global observations of large-scale traumatic events indicate increased usage of mental health services. The question then arises regarding the scope of services required in response to the mega-atrocity of October 7. OBJECTIVES: To chart the utilization of psychiatric clinical treatment services in Israel in the aftermath of the October 7 attack. METHODS: This is a retrospective cohort analysis using the electronic database from the research division of Clalit Health Services. We performed a comparative charting of mental health clinic treatments among individuals aged 15 and above, focusing on October-December 2023. These data were then compared to corresponding months over the previous five years (2018-2022). RESULTS: From October to December 2023, there was a 23.2% increase in the requests for mental health clinic treatments, compared to the same period in 2022. This surge extends a continuing upward trend in the utilization of mental health services observed since 2018. CONCLUSIONS: The study results emphasize the necessity for a responsive and flexible mental health system, to address immediate and long-term psychiatric care needs. The insights derived from these data are crucial for policymakers and clinicians to restructure mental health services, aiming to enhance the quality and accessibility of care for the Israeli population. DISCUSSION: The consistent rise in utilization of clinical mental health services significantly intensified following October 7, 2023. This echoes trends observed in global studies, underscoring the profound and enduring effects of traumatic experiences on mental health. These insights highlight the necessity for ongoing, high-quality therapeutic services and underscores the critical need for strategic policy development and increased investment in mental health services.

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.

[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.

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.

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.

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.

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.

[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.

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.

Clozapine Rechallenge Following Neuroleptic Malignant Syndrome: A Systematic Review.

PURPOSE/BACKGROUND: Neuroleptic malignant syndrome (NMS) has been described with most antipsychotics, most commonly first generation. Clozapine has also been associated with NMS. METHODS/PROCEDURES: We conducted a systematic review to identify all studies investigating or describing (a) clozapine rechallenge following suspected NMS associated with clozapine, (b) clozapine use after suspected NMS associated with another antipsychotic, and (c) rechallenge with nonclozapine antipsychotics after suspected clozapine-associated NMS. FINDINGS/RESULTS: We identified 51 reports detailing 67 cases. Thirty-eight described clozapine administration after NMS on a nonclozapine antipsychotic; 12 described a clozapine rechallenge after an NMS on clozapine monotherapy; and 17 described the use of nonclozapine antipsychotics after an NMS on clozapine. The outcome of clozapine rechallenge was favorable (no recurrence of NMS) in 92% (n = 11) of cases after an NMS on clozapine and in 79% (n = 30) of those prescribed clozapine following NMS on a nonclozapine antipsychotic. Most (82%; n = 14) cases after NMS on clozapine had no recurrence of NMS on receiving a nonclozapine antipsychotic.No mortality was reported with any of these interventions. IMPLICATIONS/CONCLUSIONS: Our findings suggest that rechallenge following clozapine NMS is possible, and with careful risk-benefit analysis consideration, a clozapine rechallenge can be made. A publication bias in favor of cases in which rechallenge was successful is probable and is an important limitation.

Adherence to antidepressant medications is associated with reduced premature mortality in patients with cancer: A nationwide cohort study.

BACKGROUND: Depression and anxiety are common in cancer and antidepressants (AD) are efficacious treatment. The relationship between AD adherence and mortality in cancer is unclear. This study aimed to evaluate the association between adherence to AD and all-cause mortality in a population-based cohort of patients with cancer. MATERIALS AND METHODS: We conducted a 4-year historical prospective cohort study including 42,075 patients with cancer who purchased AD at least once during the study period. Adherence to AD was modeled as nonadherence (<20%), poor (20-50%), moderate (50-80%), and good (>80%) adherence. We conducted multivariable survival analyses adjusted for demographic and clinical variables that may affect mortality. RESULTS: During 1,051,489 person-years at risk follow-up, the adjusted hazard ratios (HR) for mortality were 0.89 (95% confidence interval [CI]: 0.83-0.95), 0.77 (95% CI: 0.66-0.72), and 0.80 (95% CI: 0.76-0.85) for the poor, moderate, and good adherence groups, respectively, compared to the nonadherent group. Analysis of the entire sample and a subgroup with depression, for cancer subtypes, revealed similar patterns for breast, colon, lung, and prostate cancers, but not for melanoma patients. Multivariate predictors of premature mortality included male gender (HR 1.48 [95% CI: 1.42-1.55]), current/past smoking status (HR 1.1, [95% CI: 1.04-1.15]; P < .0001), low socioeconomic status (HR 1.1, [95% CI: 1.03-1.17]; P < .0001) and more physical comorbidities. CONCLUSIONS: The present study is the first to demonstrate that higher adherence to AD is associated with a decrease of all-cause mortality in a large nationwide cohort of cancer patients. Our data add to the pressing need to encourage adherence to AD among cancer patients.

Simple Schizophrenia: A Forgotten Diagnosis in Psychiatry.

Clustering of symptoms to characterize simple schizophrenia is still debated, and support is needed for the characterization of simple schizophrenia as a syndrome. We conducted a systematic review to identify all cases of simple schizophrenia published until December 2017. We identified 42 cases of simple schizophrenia, 57% of which met all three diagnostic criteria (ICD-10, DSM-4 research criteria, and Black and Boffeli's criteria for simple schizophrenia). The mean age at first contact with clinical services was 30.1 (SD = 11.6) years, with a mean delay of 7.4 (SD = 6.8) years from symptom onset to first presentation. An insidious onset and negative symptoms were characteristic features in all cases. Social withdrawal, alogia, blunted affect, lack of initiative/interest, and functional impairment were found in more than 85% of cases. Our findings contribute to greater awareness and understanding of simple schizophrenia, and have the potential to reawaken interest in this clinically distinct subgroup.

Childhood methylphenidate adherence as a predictor of antidepressants use during adolescence.

Methylphenidate (MPH) is a common and effective treatment for attention deficit hyperactivity disorder (ADHD), but little is known about the relationship between early childhood intake of MPH and onset of antidepressant treatment during adolescence. The study aimed to examine whether adherence to MPH during early childhood predicts the initiation of antidepressants during adolescence. This is a 12-year historical prospective nationwide cohort study of children enrolled in an integrated care system who were first prescribed MPH between the ages of 6 and 8 years (N = 6830). We tested for an association between their adherence to MPH during early childhood (as indicated by medication possession ratio from MPH onset through the age of twelve) and the likelihood of being prescribed any antidepressant during adolescence (age 13-18). As all country citizens are covered by mandatory health insurance, and full services are provided by one of the four integrated care systems, data regarding patients' diagnoses, prescriptions, and medical purchases are well documented. Logistic regression analysis indicated that those with higher adherence to MPH had a 50% higher risk (95% CI 1.16-1.93) of receiving antidepressants during adolescence when controlling for other comorbid psychiatric conditions and parental use of antidepressants. In this large-scale longitudinal study, MPH adherence during early childhood emerged as a predictor for antidepressant treatment during adolescence, which may reflect increased emotional and behavioral dysregulation in this group. The highly adherent patients are at higher risk and should be clinically monitored more closely, particularly into adolescence.

Cognitive Impairments in Abstinent Male Residents of a Therapeutic Community for Substance-Use Disorders: A Five-Year Retrospective Study.

BACKGROUND AND OBJECTIVES: Prior studies of residual cognitive deficits in abstinent substance-use disorder (SUD) patients, exhibited conflicting reports and a substantial patient selection bias. The aim of this study was to test the cognitive function of a sample of chronic abstinent SUD patients in a therapeutic-community. METHODS: The IntegNeuroTM cognitive test battery was used for a retrospective cross-sectional study of cognitive functioning of an unselected sample (n = 105) of abstinent male residents of a therapeutic-community. The results were compared to a large age-, gender-, and education-matched normative cohort. RESULTS: A significant negative deviance from the normal cohorts' mean was present in most of the cognitive test results and in all the cognitive domains that were tested. The most substantial deficit was found in the executive function domain (d = 1.02, 95%CI (±0.11)). Correct identification of facial emotions was significantly lower selectively in expressions of disgust and sadness. Substance-use starting at an early age (12.4 ± 0.8 years) was associated with lower performance in tests of sustained attention and impulsivity as well as with varied ability to identify correctly "negative" emotions in the emotion identification domain. CONCLUSIONS: This 5-year retrospective study demonstrates substantial cognitive impairments in an unselected sample of abstinent SUD patients. Impairment in multiple cognitive domains may lower the probability for remission and successful social integration. Early-age substance initiation may be associated with larger impairments in cognitive performance.

[THERE IS ROOM FOR IMPROVEMENT: THE RATE OF CLOZAPINE USE AMONG PATIENTS WITH SCHIZOPHRENIA IN ISRAEL].

BACKGROUND: About a third of schizophrenia patients would not have sufficient clinical response to antipsychotic treatment. The only drug approved for this population is clozapine, yet worldwide reports suggest underuse of clozapine and significant delay in initiating treatment. OBJECTIVES: To assess, for the first time in Israel, the rate of clozapine use in patients with schizophrenia. METHODS: A retrospective cohort study of "Clalit Health Services" electronic records was conducted. People diagnosed with schizophrenia (F.20 ICD 10 code) who had at least one prescription filled for clozapine were followed up between 2012 and 2014. RESULTS: Of 28,983 people diagnosed with schizophrenia, clozapine was prescribed and purchased by 1817 (6.5%) patients during the study period. In addition, 60% of patients with clozapine had polytherapy with other antipsychotic compound or lithium. Polytherapy was associated with HR of 2.1 for morality during the follow-up period. CONCLUSIONS: Clozapine is underutilized in Israel, similar to reports from other countries. Moreover, the data suggests that when treatment is given it is not optimized, as reflected by high rates of polytherapy associated with increased mortality. Using therapeutic drug monitoring, now available in Israel, for clozapine might increase clozapine dosage optimization.

Hepatitis, Interstitial Nephritis, and Pancreatitis in Association With Clozapine Treatment: A Systematic Review of Case Series and Reports.

PURPOSE/BACKGROUND: Clozapine is the criterion standard in treatment-resistant schizophrenia. We sought to review data on several inflammatory effects associated with clozapine, specifically interstitial nephritis, hepatitis, and pancreatitis. METHODS/PROCEDURES: We conducted a systematic review to identify studies, published up until December 2017, describing clozapine-induced hepatitis, nephritis, and pancreatitis. The primary objective was to characterize the clinical characteristics associated with each of the specific inflammatory reactions to clozapine. FINDINGS/RESULTS: We identified 42 cases of inflammatory reactions associated with clozapine treatment- 20 :cases of clozapine-induced hepatitis, 11 cases of nephritis, and 11 of pancreatitis. The mean (SD) age was 38.8 (11.9) years. The mean (SD) dose of clozapine used was 252.4 (133.7) mg. Time to onset of pancreatitis (17.9 [11.2] days; range 4-35 days) was shorter than that for hepatitis (34.2 [20.1] days; range, 12-90 days) and nephritis (27.9 [27.0]; range, 8-90 days) but was not statistically significant (F = 2.267, P = 0.117). The mean (SD) time to recovery was shorter for cases of pancreatitis (15.7 [18.4] days) compared with cases of hepatitis (25.9 [16.5] days) and nephritis (24.5 [18.9] days). Three cases with hepatitis died. Seven of the cases had a clozapine rechallenge (hepatitis [n = 3], nephritis [n = 1], pancreatitis [n = 3]), with 5 having a recurrence at a mean (SD) onset of 3.5 (2.5) days (range, 1-7 days); 2 hepatitis cases were successfully rechallenged. IMPLICATIONS/CONCLUSIONS: Clozapine-induced hepatitis, nephritis, and pancreatitis are uncommon adverse events, reflected in the paucity of case studies in the literature. Early recognition of the signs and symptoms of clozapine-associated hepatitis, nephritis, and pancreatitis is important, as when identified, clozapine should be urgently discontinued. Clozapine is associated with evidence of benign inflammatory processes; the extent to which hepatitis, and other inflammatory reactions, may be on a continuum with these more benign and self-limiting reactions is unclear, and this can only be resolved by prospectively following cohorts of clozapine-treated patients.

The Use of Granulocyte Colony-Stimulating Factor in Clozapine Rechallenge: A Systematic Review.

PURPOSE/BACKGROUND: Clozapine is associated with hematological abnormalities, with neutropenia and agranulocytosis of most concern. Granulocyte colony-stimulating factor (G-CSF) has been used to support clozapine rechallenge after neutropenia with the aim of maintaining the neutrophil count. This study aims to explore the practice, use, safety, and efficacy of G-CSF in this context. METHODS/PROCEDURES: We conducted a systematic review to identify all studies investigating or describing G-CSF as a prophylaxis to enable continued clozapine treatment during a rechallenge. FINDINGS/RESULTS: We identified 32 reports of patients who received G-CSF either regularly (n = 23) or as required (n = 9) to support clozapine rechallenge after an episode of neutropenia necessitating discontinuation of clozapine. Seventy-five percent (n = 24) of published cases remained on clozapine with the use of continual prophylactic G-CSF or after single G-CSF administrations (n = 8). Seventy percent (n = 16) of patients in receipt of continual prophylactic G-CSF were successfully maintained on clozapine. However, 1 of the 3 episodes of rechallenge in those with a history of severe agranulocytosis (absolute neutrophil count <0.1 × 10/L) had a recurrence of agranulocytosis at week 9. IMPLICATIONS/CONCLUSIONS: Our findings suggest that G-CSF can sometimes be safely used to support the maintenance of normal neutrophil counts and clozapine use after neutropenia. Publication bias is an important limitation, however. Also, few reports clearly documented the presence or absence of an independent nonclozapine cause of the index neutropenia, which may have increased success rates. Furthermore, adverse events were not systematically recorded. Prospective studies are needed to determine safety because if agranulocytosis occurs on clozapine while supported by G-CSF, there is no obvious alternate rescue therapy to promote granulopoiesis. From the available data, it is not possible to recommend this course of action for someone with a true clozapine agranulocytosis.

Clozapine-Associated Agranulocytosis Treatment With Granulocyte Colony-Stimulating Factor/Granulocyte-Macrophage Colony-Stimulating Factor: A Systematic Review.

PURPOSE/BACKGROUND: Clozapine is associated with hematological abnormalities, notably neutropenia, which may progress to agranulocytosis. Granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) have been used to reduce the frequency and duration of clozapine-associated neutropenia. This review aims to explore the use, efficacy, and tolerability of these cytokines in the treatment of clozapine-associated agranulocytosis. METHODS/PROCEDURES: We conducted a systematic review of published interventional and observational studies, case series, and case reports where G-CSF/GM-CSF was used to treat clozapine-associated agranulocytosis. FINDINGS/RESULTS: We identified 29 reports (40 patients). The median duration of neutrophil recovery time after stopping clozapine and starting cytokine treatment was 7 days (range, 2-13 days) for those with agranulocytosis (absolute neutrophil count < 0.5 × 10 cells/L). Ninety-four percent (n = 29) had no serious adverse reactions, and no deaths occurred. IMPLICATIONS/CONCLUSIONS: Our findings indicate that G-CSF/GM-CSF use is well tolerated and suggest that G-CSF can sometimes be safely used to reduce the duration of neutropenia associated with clozapine use. However, the interpretation of this outcome is difficult, given the likely publication bias for positive outcomes in case reports.

Association between Elevated C-Reactive Protein and Manic Polarity in Acute Psychiatric Inpatients with Affective Symptomatology.

The interplay between the immune system and behaviour is of increasing interest in psychiatry research. Specifically, accumulating data points to a link between inflammation and psychopathology, including affective symptomatology. We investigated the association between inflammation and affective polarity in psychiatric inpatients who were hospitalized due to an affective exacerbation. Data was collected retrospectively and comparisons were made between manic and depressed patients. C-reactive protein (CRP), a general laboratory marker of immune activation and inflammation, was used as a non-specific inflammatory biomarker. Age, smoking and body mass index were considered covariates. Manic polarity (n = 89) was associated with statistically significant elevated CRP levels compared to depressed polarity (n = 44, 56%; p = 0.036), after controlling for covariates. No differences were observed in CRP levels across Diagnostic and Statistical Manual of Mental Disorders-IV Edition-Text Revised psychiatric diagnoses. These findings suggest a transdiagnostic association between inflammation and manic polarity in affective inpatients.

Antipsychotic adjunctive therapy to mood stabilizers and 1-year rehospitalization rates in bipolar disorder: A cohort study.

OBJECTIVES: Antipsychotic adjunctive therapy to mood stabilizers (MSs) may improve relapse prevention; however, only a few naturalistic studies, reflecting more generalizable bipolar disorder (BD) samples, support this notion. We compared the 1-year rehospitalization rates of manic patients with bipolar I disorder (BD-I) who were discharged with MS (lithium or valproate) monotherapy or with adjunctive atypical or typical antipsychotic therapy. METHODS: A total of 201 patients with BD-I who were hospitalized with manic episodes between 2005 and 2013 were retrospectively followed for 1-year rehospitalization rates according to treatment at discharge: MS monotherapy, MS with atypical antipsychotics, and MS with typical antipsychotics. Additionally, time to rehospitalization during the 1-year period after discharge was compared between treatment groups. Multivariable survival analyses adjusted for covariates known to influence rehospitalization were conducted. RESULTS: Rehospitalization rates within 1 year were significantly lower in the MS with atypical antipsychotics group (6.3%) compared to the MS monotherapy group (24.3%, P=.008) and to the MS with typical antipsychotics group (20.6%, P=.02). Time to rehospitalization was significantly longer for the MS with atypical antipsychotics group (345.5 days) compared to the MS monotherapy group (315.1 days, P=.006) and to the MS with typical antipsychotics group (334.1 days, P=.02). The MS with atypical antipsychotics group had a significantly reduced adjusted risk of rehospitalization (hazard ratio=0.17, 95% confidence interval: 0.05-0.61, P=.007) compared to the MS monotherapy group. CONCLUSIONS: Atypical antipsychotic adjunctive therapy to MSs may be more effective than MS monotherapy in preventing rehospitalization during the 1-year period after a BD manic episode.