Eldar Hochman

Molecular pathways regulating pro-migratory effects of Hedgehog signaling

The Hedgehog proteins play a crucial role in metazoan embryo development. Constitutive activation of the pathway is associated with multiple types of cancer. Recent experimental data suggest involvement of Hedgehog signaling in vascular remodeling, germ cell migration, and axon guidance. The molecular mechanisms underlying these effects remain elusive. Here we show that yolk sac-derived endothelial cells and embryonic fibroblasts can directly respond to the Hedgehog signal by increased migration in an in vitro scratch (wound) assay. We also identify Hedgehog transcriptional target genes in these cells, many of which participate in cell migration, axon guidance, and angiogenesis processes. Inhibition of one such molecular pathway, neuropilin-flavomonooxygenase, blocks Hedgehog-induced cell migration. These findings suggest that Hedgehog signaling directly affects embryonic endothelial and fibroblast cell migration via molecules and pathways known to regulate cell migration in response to a variety of environmental cues.

Seasonal pattern of manic episode admissions among bipolar I disorder patients is associated with male gender and presence of psychotic features.

BACKGROUND Bipolar I disorder (BD-I) patients demonstrate disrupted chronobiology expressed as seasonal variation in mood symptoms. The seasonal pattern (SP) specifier of mood disorders was recently extended by the DSM-5, to be applied to manic episodes. However, the significance of seasonality of manic episodes for the course of BD-I is unknown. In the present study we sought to identify clinical and demographic features that discriminate between BD-I patients with and without SP of manic admissions. METHODS BD-I patients (n=148) admitted at least twice with the same mood exacerbation type, were retrospectively followed between 2005 and 2013. Demographic and clinical characteristics were compared between BD-I patients with or without SP of manic admissions. RESULTS SP of manic episode admissions, found in 31 (26%) of 117 BD-I patients with repeated manic episode admissions, was associated with higher rates of male gender (p=0.01), presence of psychotic features (p=0.01) and comorbid substance use disorder (p<0.05) compared to patients without SP. In a multivariate analysis, SP of manic episode admissions was associated with the presence of psychotic features (OR 8.42, 95% CI: 1.05-67.65, p<0.05) and male gender (OR 3.23, 95% CI: 1.08-9.65, p<0.05), but not with comorbidity of substance use disorder (OR 1.79, 95% CI: 0.71-4.50, p=0.24). LIMITATIONS Seasonal psychological/environmental factors contributing to the emergent of mood episodes could not be ruled out. CONCLUSIONS Our results suggest that SP of manic admissions is associated with male gender and the presence of psychotic features, thus might be associated with more severe form of the disorder.

Primary health care utilization prior to suicide: a retrospective case-control study among active-duty military personnel

OBJECTIVE About 45% of civilians who died by suicide had contact with a doctor within 1 month of death. Thus, educating primary care physicians (PCP) to detect and mitigate depression is an important suicide-prevention strategy. However, the PCP consulting rate before suicide has not been examined in a military population. We investigated the utilization of primary health care and mental health services by active-duty military personnel suicide cases prior to death in comparison to matched military controls. METHOD All suicides (N = 170) were extracted from a cohort of all active-duty Israeli military male personnel between 2002 and 2012. Applying a retrospective, nested case-control design, we compared primary care services utilization by suicide cases with demographic and occupationally matched military controls (N = 500). RESULTS Whereas 38.3% of suicide cases contacted a PCP within the last month before death, only 27.6% of suicide cases contacted a mental health specialist during their entire service time. The PCP contact rate within 1 month before death or index day did not differ between suicide cases and military controls (38.3% vs. 33.8%, χ²₁ = 1.05, P = .3). More suicide cases contacted a mental health specialist within service time than did military controls (27.6% vs. 13.6%, χ²₁ = 10.85, P = .001). CONCLUSIONS Even though PCP contact rate by military personnel who died by suicide is slightly lower than that reported for civilians who died by suicide prior to their death, it is higher than mental health specialist contact rate and higher than that by age-matched civilians who died by suicide. These results imply that PCPs education is a viable approach to suicide prevention in a military setting.

Vitamin D Supplementation in Chronic Schizophrenia Patients Treated with Clozapine: A Randomized, Double-Blind, Placebo-controlled Clinical Trial

Background While accumulating evidence suggests that vitamin D deficiency may be involved in the risk to develop schizophrenia and its outcome, there are no studies on vitamin D supplementation in this context. We sought to assess the effect of vitamin D supplementation on psychiatric, cognitive and metabolic parameters in chronic clozapine-treated schizophrenia patients. Methods This eight-week, randomized, double-blind, placebo-controlled clinical trial, recruited schizophrenia patients who had been maintained on clozapine treatment for at least 18 weeks and had low levels of vitamin D (< 75 nmol/l) and total PANSS scores > 70 (to ascertain the presence of residual symptoms). Patients were randomly allocated to either weekly oral drops of vitamin D (14,000 IU) or placebo and subsequently assessed at two-week intervals for psychosis severity, mood, cognition and metabolic profile. Results Twenty four patients were randomly assigned to vitamin D (aged 39.4 ± 9.6 years, 75% males) and the other 23 patients to the placebo arm (aged 42.5 ± 11.2 years, 60.9% males). After eight weeks, the vitamin D group exhibited a significant increase in vitamin D levels (31.4 vs − 0.4 nmol/l, p < 0.0001). There was no significant effect of vitamin D on psychotic, depressive or metabolic parameters. However, in the vitamin D group, there was a trend towards improved cognition (effect size = 0.17, significance lost following Bonferroni correction). Conclusions Vitamin D supplementation was associated with a trend towards improved cognition, but did not affect psychosis, mood or metabolic status. It is possible that the robust decrease in the PANSS scores in both groups may have obscured an effect of vitamin D supplementation.

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

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.

Association between serum levels of glutamate and neurotrophic factors and response to clozapine treatment

Clozapine is the only available therapy for about 30% of schizophrenia patients otherwise refractory to antipsychotics. Unfortunately, the mechanism of action of the drug is still unknown and there are no biomarkers that can predict a positive response to clozapine. We aimed to examine serum neurotrophins and glutamate levels as putative biomarkers for clozapine response based on the hypothesized mode-of-action of the compound. Blood samples of 89 chronic schizophrenia patients maintained on clozapine were analyzed in a cross-sectional design. Serum brain derived neurotrophic factor (BDNF), vascular endothelial growth factor (VEGF), neurotrophic growth factor (NGF), glial derived neurotrophic factor (GDNF) and glutamate were determined. Differences between responders and non-responders to clozapine and correlation between clinical and biological measures were analyzed. Our sample consisted of 54 (61%) responders and 35 (39%) non-responders. Responders had higher mean BDNF levels than non-responders (2066±814 vs. 1668±820pg/ml, p<0.05. respectively) and higher serum glutamate levels (1.61±2.2 vs. 0.66±0.9pg/ml, respectively, p<0.05). Furthermore, there was a significant correlation between serum glutamate levels and positive symptoms among the clozapine-responder group (rho=0.47, p<0.005). High serum levels of BDNF and glutamate were associated with response to clozapine, while glutamate levels correlated with the psychosis severity in clozapine responders only. Large-scale, prospective longitudinal studies are needed to support these findings and the assumption that serum glutamate and BDNF can discriminate between clozapine responders and non-responders.

The association between serum creatine kinase, mood and psychosis in inpatients with schizophrenia, bipolar and schizoaffective disorders.

Previous studies demonstrated levels of serum CK (sCK) in the majority of patients undergoing acute psychosis. Records of 1054 patients hospitalized in Geha Mental Health Center during the study period were analyzed. Of them, 743 have been diagnosed with schizophrenia (Sz), 170 with schizoaffective disorder (SzA), and 158 with bipolar disorder (BP-I). Baseline sCK and PANSS values were obtained from each patient upon admission. Our results show that LnsCK is higher in patients with BP-I in comparison with patients with SZ, but not significantly different compared to patients with SzA. A multivariate analysis using linear regression model in which LnsCK was predicted by factors such as PANSS-total and sub-scores, IM injection, BMI, gender, and age among patients at each admission, revealed that PANSS-depression was inversely associated with LnsCK level in SzA and BP-I and not in SZ. A positive association was found between PANSS-total and sCK in SzA and BP-I; however, PANSS-positive scores correlated with sCK only in SzA. After controlling for confounders, it seems that sCK level is associated with the both affective and psychotic components. Serum CK may serve as a biomarker for affective exacerbation rather than psychosis.

Association between bipolar episodes and fluid and electrolyte homeostasis: a retrospective longitudinal study

Imbalance of fluid and electrolyte homeostasis has been suggested to be associated with the neuropathological processes underlying bipolar disorder. However, longitudinal data regarding the association of bipolar episodes with fluid balance are still lacking. We hypothesized that mania may be associated with a relative fluid retention and hemodilution, and depression with a relative hemoconcentration.

Acute manic episode is associated with an increased risk of lower limb edema.

OBJECTIVE Lower limb edema (LLE) was suggested to be associated with the use of psychotropic drugs among patients suffering from severe mental illnesses; however no direct mechanism was found. Therefore, we examined the association between the occurrence of LLE and acute untreated episode leading to hospitalization. METHODS A retrospective cross-sectional study was conducted using medical charts of 2529 patients admitted to Geha Mental Health Center between 2002 and 2012. Incident cases of LLE, demographic and clinical data were retrieved. Admission clinical status was modeled as three non-overlapping groups of patients: (i) Patients with a non-affective psychosis (NAP) episode (n = 1563), (ii) patients with a manic episode (n = 366), and (iii) patients with a depressive episode (n = 600). We performed a logistic regression analysis with LLE as the dependent variable controlling for the demographic and clinical variables that may be associated with LLE. RESULTS LLE was diagnosed in 3.8% (n = 95) of the study population. The rate of LLE was 3-fold higher (χ(2) = 51.9, df = 2, p<0.001) in patients admitted with a manic episode (n = 38; 10.4%) compared to patients admitted with a NAP episode (n = 41; 2.6%) and patients admitted with a depressive episode (n = 16; 2.7%). Manic episode was associated with an increased risk for LLE compared to depressive episode (OR 8.72, 95% CI: 3.53-21.52, p<0.001) or NAP episode (OR 3.96, 95% CI: 2.16-7.26, p<0.001) after controlling for relevant confounders. CONCLUSION Acute manic episode, leading to hospitalization, is associated with an increased risk of LLE, compared to NAP or depressive episode, suggesting causal relationship between mood and fluid imbalance. Yet, future prospective studies are needed to rule out the contribution of physical agitation and lithium treatment.

Low adherence to antidepressants is associated with increased mortality following stroke: A large nationally representative cohort study

Post stroke depression is common and pervasive. In the general population, there has been some controversy that antidepressant (AD) medication is associated with premature mortality. Data is still lacking regarding the association between adherence to antidepressants (AD) and all-cause mortality. In this retrospective analysis of a population-based cohort of patients, 32,361 post-stroke patients who purchased at least one AD were followed for all-cause mortality over 4-years. Adherence to AD was measured as a ratio between dispensed and prescribed durations and was modeled as: non-adherence (<20%, n=8619), poor (20-50%, n=5108), moderate (50-80%, n=5656), and good (>80%, n=12,978) adherence. Multivariable survival analyses, adjusted for demographic and clinical variables including physical comorbidities known to influence mortality, were conducted. Unadjusted mortality rates were 16.5%, 20.2%, 22.2% and 23.7% in those classified as non-adherent, poor, moderate and good adherence respectively (χ2=174.6, p<0.0001). In the adjusted model, the non-adherent and poor adherence groups had significantly increased mortality Hazard Ratios (HR) of 1.25 (95% CI: 1.17-1.33) and 1.17 (95% CI: 1.09-1.26) respectively compared to the good adherence group. This nationally representative data suggests that poor adherence to AD is associated with increased all-cause mortality among people who had a stroke. Given our findings and the high prevalence of anxiety and depression along with AD effectiveness, efforts to promote AD adherence in this population may be warranted in clinical practice.