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.

A Potential Boron Neutron Capture Therapy Agent Selectively Suppresses High-Grade Glioma: In Vitro and in Vivo Exploration.

Glioblastoma (GBM), as the most central nervous system (CNS) intractable disease, has spoiled millions of lives due to its high mortality. Even though several efforts have been made, the existing treatments have had limited success. In this sense, we studied a lead compound, the boron-rich selective epidermal growth factor receptor (EGFR)-inhibitor hybrid 1, as a potential drug for GBM treatment. For this end, we analyzed the in vitro activity of hybrid 1 in a glioma/primary astrocytes coculture, studying cellular death types triggered by treatment with this compound and its cellular localizations. Additionally, hybrid 1 concentrated boron in glioma cells selectively and more effectively than the boron neutron capture therapy (BNCT)-clinical agent 10B-l-boronophenylalanine and thus displayed a better in vitro-BNCT effect. This encouraged us to analyze hybrid 1 in vivo. Therefore, immunosuppressed mice bearing U87 MG human GBM were treated with both 1 and 1 encapsulated in a modified liposome (recognized by brain-blood barrier peptide transporters), and we observed a potent in vivo per se antitumor activity (tumor size decrease and animal survival increase). These data demonstrate that 1 could be a promising new targeted therapy for GBM.

Neutrophil to-lymphocyte and platelet-to-lymphocyte ratios as biomarkers for suicidal behavior in children and adolescents with depression or anxiety treated with selective serotonin reuptake inhibitors.

BACKGROUND: Both the neutrophil/lymphocyte ratio (NLR) and the platelet/lymphocyte ratio (PLR) have been proposed as biomarkers of suicidal risk in adults with depression. We examined whether these ratios may be considered biomarkers for suicidal behavior in young patients with major depressive or anxiety disorders before treatment with selective serotonin reuptake inhibitors (SSRIs), or as biomarkers for the adverse event of SSRI-associated suicidality. METHODS: Children and adolescents meeting criteria for major depressive or anxiety disorder were recruited. Serum levels of three pro-inflammatory cytokines (TNF-α, IL-6, IL-1ß) were assessed; and NLR and PLR calculated, from blood samples collected at baseline and after 8 weeks treatment with SSRI. A Mann-Whitney test was performed to evaluate differences in NLR and PLR between children with and without a history of a suicide attempt prior to treatment. We compared hematological parameters before and after treatment, and between children who developed SSRI-associated suicidality versus children without treatment emergent suicidality. RESULTS: Among 91 children and adolescents (aged 13.9 ± 2.4 years), baseline NLR and PLR were significantly higher among those with a history of a suicide attempt versus those without such history. Statistically significant correlations were found for the suicide ideation subscale in the Columbia suicide severity rating scale with both baseline NLR and PLR. Baseline NLR and PLR were similar in children who did and did not develop SSRI-associated suicidality after 8 weeks. In the final logistic regression model (χ2 = 18.504, df = 4, p value = 0.001), after controlling for sex, depression severity and IL-6 levels, NLR was significantly associated with a past suicide attempt (ß = 1.247, p = 0.019; OR [95% CI] = 3.478 [1.230-9.841]), with a NLR cut-off value of = 1.76 (area under the curve = 0.75 (95% CI = 0.63-0.88, sensitivity = 73%, and specificity = 71%, p value = 0.003). CONCLUSIONS: High NLR and PLR values may be associated with suicidal behavior in depressed and anxious children and adolescents. NLR appears as a better predictor of suicide attempt than PLR, and thus may be a useful biomarker of suicidality in young patients with depression or anxiety.

Liposome-based targeting of dopamine to the brain: a novel approach for the treatment of Parkinson's disease.

Delivery of drugs into the brain is poor due to the blood brain barrier (BBB). This study describes the development of a novel liposome-based brain-targeting drug delivery system. The liposomes incorporate a diacylglycerol moiety coupled through a linker to a peptide of 5 amino acids selected from amyloid precursor protein (APP), which is recognized by specific transporter(s)/receptor(s) in the BBB. This liposomal system enables the delivery of drugs across the BBB into the brain. The brain-directed liposomal system was used in a mouse model of Parkinson's disease (PD). Intra-peritoneal (IP) administration of liposomes loaded with dopamine (DA) demonstrated a good correlation between liposomal DA dose and the behavioral effects in hemiparkinsonian amphetamine-treated mice, with an optimal DA dose of 60 µg/kg. This is significantly lower dose than commonly used doses of the DA precursor levodopa (in the mg/kg range). IP injection of the APP-targeted liposomes loaded with a DA dose of 800 µg/kg, resulted in a significant increase in striatal DA within 5 min (6.9-fold, p < 0.05), in amphetamine-treated mice. The increase in striatal DA content persisted for at least 3 h after administration, which indicates a slow DA release from the delivery system. No elevation in DA content was detected in the heart or the liver. Similar increases in striatal DA were observed also in rats and mini-pigs. The liposomal delivery system enables penetration of compounds through the BBB and may be a candidate for the treatment of PD and other brain diseases.

Complex Effects of Sertraline and Citalopram on In Vitro Murine Breast Cancer Proliferation and on In Vivo Progression and Anxiety Level.

Some selective serotonin reuptake inhibitors (SSRIs), primarily sertraline, demonstrate anti-proliferative activity in malignant cell-lines and in xenografted mouse models of colorectal tumor. There is, however, a paucity of comparative studies on the anti-tumor effects of SSRIs. We compared the in vitro and in vivo effects of sertraline and citalopram on murine 4T1 breast cancer. Grafted mice were used to determine the rate of tumor growth and survival as well as the impact of stress and antidepressant treatment on tumor progression and mortality and on pro-inflammatory cytokines. Sertraline, in the micromolar range, but not citalopram, induced a significant in vitro concentration-dependent inhibition of murine 4T1 cell proliferation and splenocyte viability. In contrast, sertraline (10 mg/kg/d), enhanced in vivo tumor growth. Contrary to the study's hypothesis, chronic mild stress did not modify tumor growth in grafted mice. The in vitro effects of sertraline on tumor growth seem to be the opposite of its in vivo effects. The impact of sertraline treatment on humans with breast cancer should be further investigated.

Liposomal Carrier Conjugated to APP-Derived Peptide for Brain Cancer Treatment.

Brain tumors are hard to treat with the currently available therapy. The major obstacle in the treatment of brain tumors is the lack of therapeutic strategies capable to penetrate the blood-brain barrier (BBB). The BBB is an endothelial interface that separates the brain from the circulatory blood system and prevents the exposure of the central nervous system (CNS) to circulating toxins and potentially harmful compounds. Unfortunately, the BBB prevents also the penetration of therapeutic compounds into the brain. We present here a drug-delivery liposomal carrier, conjugated to a peptide inserted in the liposomal membrane, which is putatively recognized by BBB transporters. The peptide is a short sequence of 5 amino acids (RERMS) present in the amyloid precursor protein (APP). This APP-targeted liposomal system was designed specifically for transporting compounds with anti-cancer activity via the BBB into the brain in an effective manner. This drug-delivery liposomal carrier loaded with the anti-cancer compounds temozolomide (TMZ), curcumin, and doxorubicin crossed the BBB in an in vitro model as well as in vivo (mice model). In the in vitro model, the targeted liposomes crossed the BBB model fourfold higher than the non-targeted liposomes. Labeled targeted liposomes penetrated the brain in vivo 35% more than non-targeted liposomes. Treatment of mice that underwent intracranial injection of human U87 glioblastoma, with the targeted liposomes loaded with the three tested anti-cancer agents, delayed the tumor growth and prolonged the mice survival in a range of 45% -70%. It appears that the targeted liposomal drug-delivery system enables better therapeutic efficacy in a SCID mouse model of glioblastoma compared to the corresponding non-targeted liposomes and the free compounds.

Regulatory effect of lithium on hippocampal blood-brain barrier integrity in a rat model of depressive-like behavior.

OBJECTIVES: Recent evidence has associated mood disorders with blood-brain barrier (BBB)/ neurovascular unit (NVU) dysfunction, and reduction in blood vessels coverage by the water channel aquaporin-4 (AQP4) immunoreactive astrocytes. Lithium is an established treatment for mood disorders, yet, its mechanism of action is partially understood. We investigated the effects of lithium on BBB integrity and NVU-related protein expression in chronic mild stress (CMS) rat model of depressive-like behavior. METHODS: Male Wistar rats were exposed for 5 weeks to unpredictable mild stressors with daily co-administration of lithium chloride to half of the stressed and unstressed groups. Sucrose preference and open field tests were conducted to validate the depressive-like phenotype, and dynamic contrast-enhanced MRI analysis was utilized to assess BBB integrity in brain regions relevant to the pathophysiology of depression. Hippocampal AQP4 and claudin-5 expression were studied using immunofluorescence, western blot, and enzyme-linked immunosorbent assays. RESULTS: Lithium administration to the stressed rats prevented the reductions in sucrose preference and distance traveled in the open field, and normalized the stress-induced hippocampal BBB hyperpermeability, whereas lithium administration to the unstressed rats increased hippocampal BBB permeability. Additionally, lithium treatment attenuated the decrease in hippocampal AQP4 to glial fibrillary acidic protein immunoreactivity ratio in the stressed rats and upregulated hippocampal claudin-5 and BDNF proteins expression. CONCLUSIONS: Our findings suggest that lithium administration in a rat CMS model of depressive-like behavior is associated with attenuation of stressed-induced hippocampal BBB/NVU disruption. These protective effects may be relevant to the mode of action of lithium in 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.

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.

Chronic opipramol treatment extinguishes cocaine craving through Rac1 in responders: A rat model study.

Ras-related C3 botulinum toxin substrate 1 (Rac1), of the Rho small GTPase family, is a key regulator of actin cytoskeleton rearrangement and plays an important role in dendritic morphogenesis. Cocaine produces neuronal alterations, including structural changes in dendritic number and morphology. Emerging data indicate sigma-1 receptors (σ-1Rs) as a promising candidate for the prevention of cocaine craving. Opipramol is a σ-1R agonist approved in some European countries for depression and anxiety. Here we report that opipramol, mediated by Rac1, attenuates cocaine-seeking behavior in a rat model of self-administration. The opipramol effect was shown in two phases. It decreased cocaine-seeking behavior throughout the withdrawal phase and, interestingly, showed a significant reduction of cocaine-primed reinstatement in 75% of the opipramol-treated group (termed 'responders'). All opipramol-treated rats showed a decrease in σ-1R mRNA expression levels in the nucleus accumbens (NAc) versus controls. Responders also exhibited significantly decreased NAc Rac1 mRNA expression levels, compared with non-responder rats. Hence, Rac1 differentiated responders from non-responders. Rac1 correlated positively with σ-1R mRNA levels in opipramol responders. In another experiment, Rac1 inhibitor injected directly into the NAc core decreased active lever presses on the first day of extinction, indicating the critical role of Rac1 in the opipramol effect on drug seeking. We postulate that chronic activation of σ-1R, through a dynamic interaction with Rac1, may suggest a new approach to treat substance use disorder (SUD). Rac1 inhibition is a prerequisite for decreasing drug seeking and rehabilitation, and this can be achieved by opipramol, a medication that can be given during detoxification.

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.

[COGNITIVE CAPABILITIES OF PSYCHIATRIC INPATIENTS: A CHART REVIEW STUDY].

INTRODUCTION: In patients with schizophrenia the most impaired competence is cognition. However, the sociodemographic and medical contributors to the various neurocognitive deficits have yet to be determined. OBJECTIVES: To assess the impact of age, physical diseases, anticholinergic medications, gender and level of education on psychotic inpatients' cognitive capabilities. METHODS: This is a retrospective chart review. Participants: 249 (153 men and 96 women) inpatients with psychosis (schizophrenia or schizoaffective disorders) who underwent cognitive evaluation using occupational therapy tools, namely, Shulman's Clock Drawing Test (SCDT) and the Neurobehavioral Cognitive Status Examination (NCSE). RESULTS: Significant linear relationship was found between age (p<0.001), presence of relevant physical diseases (p<0.05) and level of education (p<0.001) and between cognitive performance. Anticholinergic medications and gender did not affect cognitive capabilities. CONCLUSIONS: Age, physical diseases and education, but not anticholinergics, seem to impact cognitive capabilities of inpatients with psychosis. DISCUSSION: The study indicates higher sensitivity of the Neuro-Behavioral-Cognitive Status Test than that of the Clock Drawing Test, when physical illnesses are present. Aditionally, according to the results of both tests, one may assume that a high level of education constitutes a protective element from cognitive deterioration in schizophrenia.

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.

Increased circulatory IL-6 during 8-week fluoxetine treatment is a risk factor for suicidal behaviors in youth.

OBJECTIVE: Selective serotonin reuptake inhibitors (SSRIs) are commonly used to treat anxiety and/or depression in pediatric populations. However, the response rates are low (approximately 50%). Moreover, SSRI use is frequently associated with adverse events (AE). Currently there are no available biomarkers for treatment response/AE. Identification of biomarkers predicting early response and/or AE could help maximize the benefit-risk ratio for the use of SSRIs, and accelerate matching of treatments to patients. Pro-inflammatory cytokines were proposed as potential biomarkers. METHOD: Ninety-two patients (35 boys and 57 girls) with major depressive disorder and/or anxiety disorders, aged 13.90 ±â€¯2.41 years, were treated with fluoxetine (FLX) for 8 weeks. Plasma concentrations of TNFα, IL-6, and IL-1ß were measured by enzyme linked immunosorbent assays before and after FLX treatment. Clinical response and AE were measured using several clinical scales, including the Clinical Global Impression - improvement, Children's Depression Rating Scale-Revised, the Beck Depression Inventory, the Screen for Child Anxiety Related Emotional Disorders, the Columbia suicide severity rating scale, and the Suicide Ideation Questionnaire. RESULTS: IL-6 levels increased after treatment only in the group of children who developed FLX-associated suicidality. CONCLUSION: An increase in IL-6 levels during treatment may be a risk factor for the emergence of FLX-associated suicidality (OR = 1.70). Further studies are necessary to clarify the role and mechanism(s) of this cytokine in the pathogenesis of this life-threatening AE.

A retrospective case series of electroconvulsive therapy in the management of comorbid depression and anorexia nervosa.

OBJECTIVE: Major depressive disorder (MDD) is common in anorexia nervosa (AN), associated with worse outcome and greater suicide risk. Electroconvulsive therapy (ECT) is highly effective in the treatment of MDD refractory to antidepressive treatment. We describe a case series of female adolescents with AN receiving ECT for MDD resistant to treatment and/or with severe suicide risk. METHOD: We retrospectively analyzed the files of all 30 adolescent females hospitalized in our department because of AN between 1998 and 2017 and treated with ECT. Severity of eating disorder (ED) and depressive symptoms was retrospectively assessed using the Clinical Global Impression-Severity Scale. RESULTS: Patients were severely depressed and suicidal on admission. All were resistant to antidepressants. A significant deterioration in depression, with severe suicidality, occurred from admission to pre-ECT, with concomitant improvement in ED symptoms and increase in body mass index (BMI). Significant improvement in depressive and ED symptoms and increase in BMI occurred following ECT, continuing to discharge. Adverse effects were mostly minimal. Fifty-three percentage of the patients were rehospitalized within the first year after ECT, mostly because of deterioration of depression and attempted suicide. Several years after discharge, 46.6% of the patients had no evidence of depression, suicidality, and ED-symptomatology, and another 23% had only evidence of ED symptomatology. DISCUSSION: ECT is safe and well tolerated in AN with severe comorbid treatment resistant MDD and/or with increased suicide risk. Many AN patients undergoing ECT may be remitted at long-term follow-up.

Effectiveness and side effects of psychopharmacotherapy in individuals with 22q11.2 deletion syndrome with comorbid psychiatric disorders: a systematic review.

22q11.2 deletion syndrome (22q11.2DS) is the most common microdeletion in humans and is associated with high rates of attention deficit/hyperactivity disorder (ADHD), psychotic spectrum disorders and mood and anxiety disorders. The objective of the study was to systematically review studies regarding pharmacological treatments for psychiatric disorders in individuals with 22q11.2DS and to provide practical guidelines for the psychiatric management and side effect monitoring in 22q11.2DS. A literature search was conducted using the databases PubMed, PsycINFO and Embase. Information regarding study population, drug treatment, side effect profile and efficacy for each trial was extracted. Data collection was completed on May 2018. The search identified 705 studies. A total of seven studies, describing 182 individuals, were included. Pharmacological interventions included three studies for antipsychotic treatment, two studies for stimulants, one study for selective serotonin reuptake inhibitors (SSRIs), one study for S-adenosyl-L-methionine (SAMe), and one case series for metyrosine. The presented data support the clinical impression that individuals with 22q11.2DS and comorbid psychiatric disorders are treated in a manner comparable to non-22q11.2DS individuals. However, distinct medical comorbidities common in individuals with 22q11.2DS may complicate the administration of pharmacotherapy. Further trials with RCT design, larger sample sizes and more syndrome-specific pharmacological agents are needed to improve evidence-based psychiatric care of 22q11.2DS individuals with comorbid mental disorders.

Association between prenatal exposure to a 1-month period of repeated rocket attacks and neuropsychiatric outcomes up through age 9: a retrospective cohort study.

Exposure to gestational stress is implicated in increased risk for neuropsychiatric disorders in offspring. We assessed association between prenatal exposure to a 1-month period of repeated rocket attacks during the 2006 Second Lebanon War in Northern Israel and emergence of childhood neuropsychiatric disorders from birth through 9 years of age. Children born to women who were pregnant during the war (N = 6999) were identified and compared to children in the same district born a year later (N = 7054), whose mothers were not exposed to rocket attacks during pregnancy. Multivariable regression models assessed risk for attention deficit hyperactivity disorder, autism, epilepsy, depression and/or anxiety, or any of these disorders (composite outcome) in offspring. Models controlled for multiple confounders including parents' demographics, parity, maternal use of psychotropic medications during pregnancy, post-partum depression and parental psychiatric history. Results show that exposed and comparison groups did not differ with respect to demographics, parity or psychiatric history. Exposed and comparison groups were similar with regard to gestational age and weight at birth. Multivariable models did not demonstrate an association between exposure to rocket attacks during pregnancy and neuropsychiatric outcomes by age 9. No interactions were found between exposure and gestational trimester at exposure or child's sex. Our findings suggest that in utero exposure to isolated, 1-month repeated rocket attacks on a civilian population was not associated with major neuropsychiatric outcomes in children by age 9. Future studies should evaluate whether this exposure is associated with psychiatric and/or other health-related outcomes later in life.

BDNF overexpression prevents cognitive deficit elicited by adolescent cannabis exposure and host susceptibility interaction.

Cannabis abuse in adolescence is associated with increased risk of psychotic disorders. Δ-9-tetrahydrocannabinol (THC) is the primary psychoactive component of cannabis. Disrupted-In-Schizophrenia-1 (DISC1) protein is a driver for major mental illness by influencing neurodevelopmental processes. Here, utilizing a unique mouse model based on host (DISC1) X environment (THC administration) interaction, we aimed at studying the pathobiological basis through which THC exposure elicits psychiatric manifestations. Wild-Type and dominant-negative-DISC1 (DN-DISC1) mice were injected with THC (10 mg/kg) or vehicle for 10 days during mid-adolescence-equivalent period. Behavioral tests were conducted to assess exploratory activity (open field test, light-dark box test) and cognitive function (novel object recognition test). Electrophysiological effect of THC was evaluated using acute hippocampal slices, and hippocampal cannabinoid receptor type 1 and brain-derived neurotrophic factor (BDNF) protein levels were measured. Our results indicate that THC exposure elicits deficits in exploratory activity and recognition memory, together with reduced short-term synaptic facilitation and loss of BDNF surge in the hippocampus of DN-DISC mice, but not in wild-type mice. Over-expression of BDNF in the hippocampus of THC-treated DN-DISC1 mice prevented the impairment in recognition memory. The results of this study imply that induction of BDNF following adolescence THC exposure may serve as a homeostatic response geared to maintain proper cognitive function against exogenous insult. The BDNF surge in response to THC is perturbed in the presence of mutant DISC1, suggesting DISC1 may be a useful probe to identify biological cascades involved in the neurochemical, electrophysiological, and behavioral effects of cannabis related psychiatric manifestations.

Modulatory effects of cannabinoids on brain neurotransmission.

Recreational and chronic cannabis use has been associated with a range of acute and chronic effects including; anti-nociceptive actions, anxiety, depression, psychotic symptoms and neurocognitive impairments. The mechanisms underlying cannabinoid-based drugs effects are not fully known but given the neuro-modulatory functions of the endocannabinoid system, it seems likely that agonistic activity at the cannabinoid type-1 receptors (CB1 ) might modulate the functions of other neurotransmitter systems. The present review has summarized the currently available pre-clinical and clinical data on the interactions of CB1 and cannabinoid type-2 receptors (CB2 ) with the central neurotransmitters; dopamine, serotonin, noradrenaline, GABA, glutamate and opioids. Acute and chronic exposures to cannabinoids exert pharmacological alterations in the mammalian brain that have profound implications for our understanding of the neuropharmacology of cannabinoid-based drugs and their effects on mental health and the brain. A recent emergence uses of cannabis for medical purpose together with legalization and decriminalization of cannabis and increasing use of highly potent synthetic cannabinoids raise a growing concern over the effects of cannabinoids and their interaction with other neurotransmitters on physical and mental health.