The role and mechanism of miR-425-3p regulating neuronal pyroptosis -mediated inorganic arsenic-induced generalized anxiety disorder.

Pyroptosis plays a critical role in the pathogenesis of mental disorders. However, its specific role and mechanism in arsenic (As)-induced generalized anxiety disorder (GAD) remain elusive. We utilized the data from CtdBbase, Phenopedia and DisGeNet to analyze genes that interact with arsenic poisoning and GAD. Subsequently KEGG and GO enrichment analysis were conducted to preliminatively predict the mechanism of inorganic arsenic-induced GAD. Male Wistar rats were administered water containing NaAsO2 (50, 100 µg/L) to evaluate GAD-like behavior through open field test and elevated plus maze. The expression of differential miRNAs including miR-425-3p, and pyroptosis in the prefrontal cortex of rats were detected. Furthermore, SKNSH cells were stimulated with NaAsO2 to examine the molecular changes, and then miR-425-3p mimic was transfected into SKNSH cells to detect pyroptosis in order to verify the function of miR-425-3p. Inorganic arsenic was confirmed to induce GAD-like behavior in rats, characterized by decreased locomotor activity and exploratory activities. Rats with inorganic arsenic-induced GAD exhibited reduced miR-425-3p expression levels in the prefrontal cortex and increased expression of pyroptosis-related proteins, including NF-κB, NLRP3, Caspase-1, GSDMD, IL-1ß, and IL-18. Treating with different concentrations of NaAsO2 showed that inorganic arsenic exposure downregulates miR-425-3p expression in SKNSH cells and upregulates the expression levels of pyroptosis-related proteins. Dual-luciferase reporter gene experiments demonstrated that miR-425-3p targets the NFKB1. Overexpressing miR-425-3p reversed the inorganic arsenic-induced pyroptosis in SKNSH cells by inhibiting the expression of NF-κB, NLRP3, Caspase-1, GSDMD, IL-1ß, and IL-18. Our findings suggest that inorganic arsenic exposure may induce GAD-like behavior in rats by downregulating miR-425-3p in prefrontal cortex, which targets NF-κB and regulates pyroptosis in neuronal cells.

Efficacy of Silexan in patients with anxiety disorders: a meta-analysis of randomized, placebo-controlled trials.

INTRODUCTION: We report on a meta-analysis of Silexan, a proprietary active substance produced from Lavandula angustifolia, in subthreshold anxiety, mixed anxiety and depressive disorder (MADD), and generalized anxiety disorder (GAD). METHODS: The present analyses are based on all currently completed 5 double-blind, randomized, placebo-controlled trials investigating Silexan in adult out-patients who received Silexan 1 × 80 mg/day or placebo for ten weeks according to random assignment (n = 1213). Efficacy was assessed based on the Hamilton Anxiety Rating Scale (HAMA), several anxiety self-rating scales, the Clinical Global Impression (CGI) scale, and the Short Form-36 (SF-36) health status questionnaire. RESULTS: After ten weeks' treatment, Silexan was significantly superior to placebo in reducing the HAMA total score (including the psychic and somatic anxiety sub-scores) and self-rated anxiety. Based on a ≥ 50% HAMA total score reduction, the responder rate ratio was 1.34 favoring Silexan, and the rate ratio of subjects much or very much improved according to the CGI was 1.51. Silexan was also significantly superior in improving the physical and mental health summary scores of the SF-36. There were no significant between-group differences concerning the occurrence of adverse events (AEs), serious AEs, and premature withdrawal due to AEs. CONCLUSIONS: This meta-analysis demonstrates that Silexan exerts significant anxiolytic effects in subthreshold anxiety, GAD and MADD that were consistently reflected in investigator ratings and patient-reported outcomes, including improvement of health-related life-quality, while showing favorable tolerability and safety.

Improvement of chronic HCV infection-related depression, anxiety, and neurocognitive performance in persons achieving SVR-12: A real-world cohort study.

Chronic hepatitis C virus (HCV) infection is associated with neuropsychiatric changes. Also, patients with cirrhosis may develop overt or minimal hepatic encephalopathy. Sustained virological response (SVR) with direct-acting antiviral agents (DAAs) may improve the neuropsychiatric manifestations and quality of life (QoL). Consecutive patients (with and without cirrhosis, all genders and aged 18-65 years) with hepatitis C were assessed at enrolment and at 12 weeks after therapy completion for mood (Beck's Depression Inventory [BDI]), anxiety (generalized anxiety disorder [GAD-7]), QoL (SF-36 ver.2) and computer-based tests for number connection (NCT), visual memory, Stroop test and reaction times. We recruited 385 viraemic chronic HCV patients (76.1% male, 21.0% cirrhotic, mean age 39.4 ± 14.2 years, 59.3% genotype 3, mean HCV RNA load 5.8 log). Overall SVR-12 rates were 90.6%, with cure rates 87.6% and 91.4% in patients with and without cirrhosis, respectively. Patients who achieved SVR-12 had mean percentage reduction in BDI (11.3%, p = .000), GAD (8.6%, p = .001) and Stroop test (58.4%, p = .001), with improved NCT (1.7%, p = .001), visual memory (13.7%, p = .001) and digit span (23.8%, p = .002). On multivariate logistic regression, adherence (OR, 17.5 [95% CI 2.80-110.50], p = .000), high ALT (OR 1.02 [95% CI 1.00-1.05]), and BDI score (OR 1.73 [95% CI 1.42-3.26] p = .039) predicted cure. SVR-12 was associated with improved visual memory ≥5.5 (AUC-0.708; sensitivity 62.5%, specificity 63%, p = .000) and % correct Stroop test responses >26.6% (AUC-0.918, sensitivity 94.4% specificity 80.4%, p = .000). In conclusion, given the cumulative evidence of the safety of DAAs and efficacy of improving cognitive and neuropsychological and quality-of-life outcomes irrespective of age and gender, as shown in our study, future recommendations should focus on integrated universal HCV care to enable HCV elimination.

Serotonin engages an anxiety and fear-promoting circuit in the extended amygdala.

Serotonin (also known as 5-hydroxytryptamine (5-HT)) is a neurotransmitter that has an essential role in the regulation of emotion. However, the precise circuits have not yet been defined through which aversive states are orchestrated by 5-HT. Here we show that 5-HT from the dorsal raphe nucleus (5-HTDRN) enhances fear and anxiety and activates a subpopulation of corticotropin-releasing factor (CRF) neurons in the bed nucleus of the stria terminalis (CRFBNST) in mice. Specifically, 5-HTDRN projections to the BNST, via actions at 5-HT2C receptors (5-HT2CRs), engage a CRFBNST inhibitory microcircuit that silences anxiolytic BNST outputs to the ventral tegmental area and lateral hypothalamus. Furthermore, we demonstrate that this CRFBNST inhibitory circuit underlies aversive behaviour following acute exposure to selective serotonin reuptake inhibitors (SSRIs). This early aversive effect is mediated via the corticotrophin-releasing factor type 1 receptor (CRF1R, also known as CRHR1), given that CRF1R antagonism is sufficient to prevent acute SSRI-induced enhancements in aversive learning. These results reveal an essential 5-HTDRN→CRFBNST circuit governing fear and anxiety, and provide a potential mechanistic explanation for the clinical observation of early adverse events to SSRI treatment in some patients with anxiety disorders.

Association between traffic-related air pollution and anxiety hospitalizations in a coastal Chinese city: are there potentially susceptible groups?

Motor vehicle exhaust emissions have become the main source of urban air pollution in China, but few studies have explored the association of short-term exposure to traffic-related air pollutants (TRAPs) with anxiety disorders. Thus, we used an overdispersed, generalized additive model (GAM) to investigate the association between TRAPs and hospital admissions (HAs) for anxiety in Qingdao, a coastal Chinese city with high vehicle ownership. In addition, stratified analyses were performed by gender, age, season and hospitalization frequency (first admission and readmission). A positive association between TRAPs and HAs for anxiety was observed. Both inhalable particulate matter (PM10) and nitrogen dioxide (NO2) showed significant effects at lag 3 in the single-day lag structure, and each 10 µg/m3 increase in the concentrations was significantly associated with increases of 0.88% [95% confidence interval (CI): 0.04%, 1.72%] for PM10 and 2.74% (0.45%, 5.08%) for NO2 on anxiety hospitalizations. For fine particulate matter (PM2.5) and carbon monoxide (CO), the strongest effects were found at lag05 and lag04 [2.67% (0.77%, 4.62%) and 0.19% (0.04%, 0.34%), respectively] in the multiday lag structure. The estimates of PM2.5 were relatively robust after adjusting for other pollutants in the two-pollutant model. Stratified analyses indicated that the associations were stronger in females and younger individuals (<45 in age) than in males and elderly individuals (≥45 in age). Furthermore, the effects of PM2.5 and CO were most obvious during the cold season. Regarding hospitalization frequency, only PM2.5 was found to have a significant effect in the first-admission group. The results showed that short-term exposure to TRAPs, especially to PM2.5, was significantly associated with the increased risk of daily HAs for anxiety, which can help clinicians and policymakers better understand the effects of TRAPs to implement targeted interventions.

[Effect of the direct healthcare professional communication on citalopram and escitalopram drug utilization for inpatient treatment of anxiety disorders]. / Effekt der Rote-Hand-Briefe zu Citalopram und Escitalopram auf Verordnungszahlen bei der stationären Behandlung von Angsterkrankungen.

BACKGROUND: In 2011, direct healthcare professional communication (DHPC) letters on citalopram and escitalopram were sent out to address the risk of QTc prolongation in the ECG. Healthcare professionals were informed about a reduction of the maximum recommended daily dose. Furthermore, a contraindication for QTc-prolonging co-medication was given. Previous studies noted that these instructions were implemented incompletely. AIM: For the first time, this study analyzed how the DHPC affected the prescription of citalopram and escitalopram in patients with anxiety disorders. METHODS: Drug utilization data from the project "Arzneimittelsicherheit in der Psychiatrie e. V." (AMSP) was used to examine whether the proportion of patients treated with a higher-than-recommended daily dose ("high dose") and the proportion of patients with QTc-prolonging co-medication would decrease post-DHPC (combined category of citalopram/escitalopram). RESULTS: Drug utilization data of n = 364 patients pre- and n = 262 patients post-DHPC were compared. The proportion of patients with high dose declined from 10.7% to 5.4% (p = 0.019). The proportion of patients with QTc-prolonging co-medication did not change significantly from pre- (54.7%) to post-DHPC (51.5%, p = 0.437). DISCUSSION: In accordance with previous studies, the proportion of high-dose patients decreased after DHPC publication while the proportion of patients with QTc-prolonging co-medication remained widely unchanged. The specific recommendation on daily dosage seems to have been better implemented than the broadly formulated contraindication of QTc-prolonging co-medication. Hence, DHPCs should be written precisely and give advice for specific clinical situations.

Paternal exposure to excessive methionine altered behavior and neurochemical activities in zebrafish offspring.

An increase in plasma L-methionine (Met) levels, even if transitory, can cause important toxicological alterations in the affected individuals. Met is essential in the regulation of epigenetic mechanisms and its influence on the subsequent generation has been investigated. However, few studies have explored the influence of a temporary increase in Met levels in parents on their offspring. This study evaluated the behavioral and neurochemical effects of parental exposure to high Met concentration (3 mM) in zebrafish offspring. Adult zebrafish were exposed to Met for 7 days, maintained for additional 7 days in tanks that contained only water, and then used for breeding. The offspring obtained from these fish (F1) were tested in this study. During the early stages of offspring development, morphology, heart rate, survival, locomotion, and anxiety-like behavior were assessed. When these animals reached the adult stage, locomotion, anxiety, aggression, social interaction, memory, oxidative stress, and levels of amino acids and neurotransmitters were analyzed. F1 larvae Met group presented an increase in the distance and mean speed when compared to the control group. F1 adult Met group showed decreased anxiety-like behavior and locomotion. An increase in reactive oxygen species was also observed in the F1 adult Met group whereas lipid peroxidation and antioxidant enzymes did not change when compared to the control group. Dopamine, serotonin, glutamate, and glutathione levels were increased in the F1 adult Met group. Taken together, our data show that even a transient increase in Met in parents can cause behavioral and neurochemical changes in the offspring, promoting transgenerational effects.

Activation of AMPK by metformin improves withdrawal signs precipitated by nicotine withdrawal.

Cigarette smoking is the leading cause of preventable disease and death in the United States, with more persons dying from nicotine addiction than any other preventable cause of death. Even though smoking cessation incurs multiple health benefits, the abstinence rate remains low with current medications. Here we show that the AMP-activated protein kinase (AMPK) pathway in the hippocampus is activated following chronic nicotine use, an effect that is rapidly reversed by nicotine withdrawal. Increasing pAMPK levels and, consequently, downstream AMPK signaling pharmacologically attenuate anxiety-like behavior following nicotine withdrawal. We show that metformin, a known AMPK activator in the periphery, reduces withdrawal symptoms through a mechanism dependent on the presence of the AMPKα subunits within the hippocampus. This study provides evidence of a direct effect of AMPK modulation on nicotine withdrawal symptoms and suggests central AMPK activation as a therapeutic target for smoking cessation.

Smoking and Neuropsychiatric Disease-Associations and Underlying Mechanisms.

Despite extensive efforts to combat cigarette smoking/tobacco use, it still remains a leading cause of global morbidity and mortality, killing more than eight million people each year. While tobacco smoking is a major risk factor for non-communicable diseases related to the four main groups-cardiovascular disease, cancer, chronic lung disease, and diabetes-its impact on neuropsychiatric risk is rather elusive. The aim of this review article is to emphasize the importance of smoking as a potential risk factor for neuropsychiatric disease and to identify central pathophysiological mechanisms that may contribute to this relationship. There is strong evidence from epidemiological and experimental studies indicating that smoking may increase the risk of various neuropsychiatric diseases, such as dementia/cognitive decline, schizophrenia/psychosis, depression, anxiety disorder, and suicidal behavior induced by structural and functional alterations of the central nervous system, mainly centered on inflammatory and oxidative stress pathways. From a public health perspective, preventive measures and policies designed to counteract the global epidemic of smoking should necessarily include warnings and actions that address the risk of neuropsychiatric disease.

Brain Functional Connectivity Correlates of Response in the 7.5% CO2 Inhalational Model of Generalized Anxiety Disorder: A Pilot Study.

BACKGROUND: The 7.5% CO2 inhalational model can be used to explore potential treatments for generalized anxiety disorder. However, it is unknown how inter-individual variability in the functional architecture of negative affective valence systems might relate to anxiogenic response in this model. METHODS: A total of 13 healthy volunteers underwent functional magnetic resonance imaging during a passive emotional face perception task. We explored task-evoked functional connectivity in the potential threat system through generalized psychophysiological interaction analysis. Within 7 days, these participants underwent prolonged 7.5% CO2 inhalation, and results from the generalized psychophysiological interaction analysis were correlated with CO2 outcome measures. RESULTS: Functional connectivity between ventromedial prefrontal cortex and right amygdala positively correlated with heart rate and subjective anxiety, while connectivity between midcingulate cortex and left amygdala negatively correlated with anxiety during CO2 challenge. CONCLUSIONS: Response to CO2 challenge correlated with task-evoked functional connectivity in the potential threat system. Further studies should assess whether this translates into clinical populations.

The association of depressive symptoms, personality traits, and sociodemographic factors with health-related quality of life and quality of life in patients with advanced-stage lung cancer: an observational multi-center cohort study.

BACKGROUND: Identification of patient-related factors associated with Health-Related Quality of Life (HRQoL) and Quality of Life (QoL) at the start of treatment may identify patients who are prone to a decrease in HRQoL and/or QoL resulting from chemotherapy. Identification of these factors may offer opportunities to enhance patient care during treatment by adapting communication strategies and directing medical and psychological interventions. The aim was to examine the association of sociodemographic factors, personality traits, and depressive symptoms with HRQoL and QoL in patients with advanced-stage lung cancer at the start of chemotherapy. METHODS: Patients (n = 151) completed the State-Trait Anxiety Inventory (trait anxiety subscale), the Neuroticism-Extraversion-Openness-Five Factor Inventory (NEO-FFI), the Center for Epidemiologic Studies Depression (CES-D), the World Health Organization Quality of Life-BREF (WHOQOL-BREF), and the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30). Simple linear regression analyses were performed to select HRQoL and QoL associated factors (a P ≤ 0.10 was used to prevent non-identification of important factors) followed by multiple linear regression analyses (P ≤ 0.05). RESULTS: In the multiple regression analyses, CES-D score (ß = - 0.63 to - 0.53; P-values < 0.001) was most often associated with the WHOQOL-BREF domains and general facet, whereas CES-D score (ß = - 0.67 to - 0.40; P-values < 0.001) and Eastern Cooperative Oncology Group (ECOG) performance status (ß = - 0.30 to - 0.30; P-values < 0.001) were most often associated with the scales of the EORTC QLQ-C30. Personality traits were not related with HRQoL or QoL except for trait anxiety (Role functioning: ß = 0.30; P = 0.02, Environment: ß = - 0.39; P = 0.007) and conscientiousness (Physical health: ß = 0.20; P-value < 0.04). CONCLUSIONS: Higher scores on depressive symptoms and ECOG performance status were related to lower HRQoL and QoL in patients with advanced-stage non-small cell lung cancer. Supportive care interventions aimed at improvement of depressive symptoms and performance score may facilitate an increase of HRQoL and/or QoL during treatment.

Systemic and Local Corticosteroid Use Is Associated with Reduced Executive Cognition, and Mood and Anxiety Disorders.

BACKGROUND: Use of local corticosteroids, especially the inhaled types, has increasingly been associated with systemic uptake and consequent adverse effects. In this study, we assessed the associations between the use of different corticosteroid types with cognitive and neuropsychiatric adverse effects related to high glucocorticoid exposure. METHODS: In 83,592 adults (mean age 44 years, 59% women) of the general population (Lifelines Cohort Study), we analyzed the relationship between corticosteroid use with executive cognitive functioning (Ruff Figural Fluency Test), and presence of mood and anxiety disorders (Mini-International Neuropsychiatric Interview survey). We performed additional exploration for effects of physical quality of life (QoL; RAND-36), and inflammation (high-sensitive C-reactive protein [CRP]). RESULTS: Cognitive scores were lower among corticosteroid users, in particular of systemic and inhaled types, when compared to nonusers. Users of inhaled types showed lower cognitive scores irrespective of physical QoL, psychiatric disorders, and high-sensitive CRP. Overall corticosteroid use was also associated with higher likelihood for mood and anxiety disorders. Users of inhaled corticosteroids were more likely to have mood disorders (OR 1.40 [95% CI 1.19-1.65], p < 0.001) and anxiety disorders (OR 1.19 [95% CI 1.06-1.33], p = 0.002). These findings were independent of physical QoL. A higher likelihood for mood disorders was also found for systemic users whereas nasal and dermal corticosteroid users were more likely to have anxiety disorders. CONCLUSIONS: Commonly used local corticosteroids, in particular inhaled types, and systemic corticosteroids are associated with reduced executive cognitive functioning and a higher likelihood of mood and anxiety disorders in the general adult population.

Association of Megestrol Use With the Development of New Psychiatric Diagnoses.

OBJECTIVE: To analyze the risk of megestrol, a glucocorticoid and progesterone receptor agonist used to enhance appetite, on the development of a new psychiatric diagnosis. DESIGN AND PARTICIPANTS: Deidentified data of megestrol (n = 706) and propensity score-matched comparison (age, gender, and body mass index) patients (n = 2,118) from January 1, 2001 to June 30, 2018 were obtained from the UT Southwestern patient database. Data were analyzed using a series of conditional binary logistic regressions controlling for comorbidities, pre-existing psychiatric disorders, and number of patient encounters. SETTING: A large academic medical center database of megestrol-treated patients and matched comparison patients was used. MEASUREMENTS AND RESULTS: The regression model showed that megestrol was significantly associated with developing a new psychiatric diagnosis (B = 1.28, Wald χ21 = 83.12, odds ratio [OR] = 3.60, p <0.001). In subgroup analyses, development of cognitive (B = 2.42, Wald χ21 = 16.09, OR = 11.30, p <0.001), mood (B = 1.31, Wald χ21 = 40.38, OR = 3.70, p <0.001), and anxiety (B = 1.72, Wald χ21 = 45.28, OR = 5.60, p <0.001) disorders were also associated with megestrol use. CONCLUSIONS: Patients taking megestrol were significantly more likely to develop a new psychiatric diagnosis than comparison patients. Highest risks were associated with the development of cognitive diagnoses. The findings suggest that megestrol, like other glucocorticoid agonists, is associated with an increased risk of developing a psychiatric disorder. This risk should be considered when determining the risk-to-benefit ratio of megestrol use in patients.

New-onset insomnia among cancer patients undergoing chemotherapy: prevalence, risk factors, and its correlation with other symptoms.

STUDY OBJECTIVES: Although insomnia is common among cancer patients, its prevalence remains variable, and its risk factors and correlation with other cancer-related symptoms are not fully explored in the literature. This study aims to determine the prevalence and severity of insomnia as well as risk factors and sleep-related symptom clusters in a sample of cancer patients. METHODS: A cross-sectional survey was conducted collecting data from 213 cancer patients undergoing chemotherapy (age = 53.1 ± 11.3 years, 60% female). Insomnia was measured using the Insomnia Severity Index, a sleep log, and Actigraph, while symptoms were assessed using the Memorial Symptom Assessment Scale and the Hospital Anxiety and Depression Scale. Quality of life was measured with the Functional Assessment of Cancer Therapy-General. RESULTS: Of the participants, 42.8% reported insomnia, with 31.9% of those with insomnia reporting severe insomnia. Insomnia occurrence and severity were not correlated with the participants' characteristics, cancer-related or treatment-related factors, only with the participants' anxiety/depression scores. Principal component analysis showed that insomnia, depression, and anxiety formed a symptom cluster (p < 0.001). There was no difference between sleep parameters measured by Actigraphy in insomnia and non-insomnia participants. CONCLUSION: This study demonstrated that the prevalence of insomnia was high and indicated a symptom cluster of insomnia, depression, and anxiety. Therefore, interventions to reduce this symptom cluster may benefit cancer patients who are trying to manage these symptoms.

Incidence of diagnosed pediatric anxiety disorders and use of prescription drugs: a nation-wide registry study.

The aim of this study was to calculate time trends in incidence of diagnosed anxiety disorders, including obsessive-compulsive disorder, and post-traumatic stress disorder, and to examine changes in use of prescribed drugs in the Norwegian pediatric population. Furthermore, we aimed to investigate whether comorbid mental disorders are associated with the use of prescribed drugs. Nation-wide registries with data from 2008 to 2015 were used, covering diagnostic data from primary health care [the Norwegian database for the control and reimbursement of health expenses (KUHR)] and secondary health care [the Norwegian Patient registry (NPR)], and data on prescribed drugs [the Norwegian prescription database, (NorPD)]. Data from the two latter were linked. During the period 2010-2015, 19,154 children and adolescents (61% girls) received a first diagnosis of anxiety disorders in primary care. The corresponding number from secondary care was 17,115 (61% girls). The incidence of diagnosed anxiety disorders increased over time, especially in girls, with an overall raise of ~ 2 per 1000 children across 2010-2015. Anti-anxiety drugs were used by < 12% of diagnosed children and < 25% of diagnosed adolescents, mainly by those with several contacts with the specialist health care system. There was no strong indications of an increase over time. Of other drugs, the most frequently prescribed were hypnotics and psychostimulants. Psychiatric comorbidity (33-55%) contributed to the use of drugs, including anti-anxiety drugs. The incidence of diagnosed anxiety disorders increased from 2010 to 2015, but the percentage using anti-anxiety drugs was stable. Drug use appears to be in line with the Norwegian guidelines.

Cannabis Use and the Risk for Psychosis and Affective Disorders.

Objective: This review discusses the relationship between cannabis use and psychotic, bipolar, depressive, and anxiety disorders, as well as suicide. It summarizes epidemiological evidence from cross-sectional and long-term prospective studies and considers possible etiological mechanisms. Methods: Systematic reviews and methodologically robust studies in the field (from inception to February 2019) were identified using a comprehensive search of Medline, PsychINFO, and Embase and summarized using a narrative synthesis. Results: Consistent evidence, both from observational and experimental studies, has confirmed the important role of cannabis use in the initiation and persistence of psychotic disorders. The size of the effect is related to the extent of cannabis use, with greater risk for early cannabis use and use of high-potency varieties and synthetic cannabinoids. Accumulating evidence suggests that frequent cannabis use also increases the risk for mania as well as for suicide. However, the effect on depression is less clear and findings on anxiety are contradictory with only a few methodologically robust studies. Furthermore, the relationship with common mental disorders may involve reverse causality, as depression and anxiety are reported to lead to greater cannabis consumption in some studies. Pathogenetic mechanisms focus on the effect of tetrahydrocannabinol (THC, the main psychoactive ingredient of cannabis) interacting with genetic predisposition and perhaps other environmental risk factors. Cannabidiol (CBD), the other important ingredient of traditional cannabis, ameliorates the psychotogenic effects of THC but is absent from the high-potency varieties that are increasingly available. Conclusions: The evidence that heavy use of high-THC/low-CBD types of cannabis increases the risk of psychosis is sufficiently strong to merit public health education. Evidence of similar but smaller effects in mania and suicide is growing, but is not convincing for depression and anxiety. There is much current interest in the possibility that CBD may be therapeutically useful.

HIV-1 Tat Dysregulates the Hypothalamic-Pituitary-Adrenal Stress Axis and Potentiates Oxycodone-Mediated Psychomotor and Anxiety-Like Behavior of Male Mice.

Human immunodeficiency virus (HIV) is associated with co-morbid affective and stress-sensitive neuropsychiatric disorders that may be related to dysfunction of the hypothalamic-pituitary-adrenal (HPA) stress axis. The HPA axis is perturbed in up to 46% of HIV patients, but the mechanisms are not known. The neurotoxic HIV-1 regulatory protein, trans-activator of transcription (Tat), may contribute. We hypothesized that HPA dysregulation may contribute to Tat-mediated interactions with oxycodone, a clinically-used opioid often prescribed to HIV patients. In transgenic male mice, Tat expression produced significantly higher basal corticosterone levels with adrenal insufficiency in response to a natural stressor or pharmacological blockade of HPA feedback, recapitulating the clinical phenotype. On acute exposure, HIV-1 Tat interacted with oxycodone to potentiate psychomotor and anxiety like-behavior in an open field and light-dark transition tasks, whereas repeated exposure sensitized stress-related psychomotor behavior and the HPA stress response. Pharmacological blockade of glucocorticoid receptors (GR) partially-restored the stress response and decreased oxycodone-mediated psychomotor behavior in Tat-expressing mice, implicating GR in these effects. Blocking corticotrophin-releasing factor (CRF) receptors reduced anxiety-like behavior in mice that were exposed to oxycodone. Together, these effects support the notion that Tat exposure can dysregulate the HPA axis, potentially raising vulnerability to stress-related substance use and affective disorders.

Hormonal Contraceptives and Mood: Review of the Literature and Implications for Future Research.

PURPOSE OF REVIEW: We examine recent studies that investigate the effects of hormonal contraception on mood in different populations of women, including women in the general population and women with diagnosed psychiatric and gynecologic disorders. We address the mechanisms of several types of hormonal contraceptives and assess how these may affect mood and gynecologic disorders. RECENT FINDINGS: The effects of hormonal contraceptives seem to be most relevant in selected subsets of women, as they may promote improved mental health in particular psychiatric disorders such as PMDD. Currently, there is no consistent evidence for negative effects of most hormonal contraceptives in the general population. Even though some studies reveal that certain individuals appear susceptible to negative mood effects from some forms of hormonal contraceptives, more research is needed to better identify these susceptible individuals.

Cannabis and mental illness: a review.

With the increasing push to legalize cannabis in Western nations, there is a need to gage the potential impact of this policy change on vulnerable populations, such as those with mental illness, including schizophrenia, mood, and anxiety disorders. This is particularly important as there are strong motives in these individuals to seek short-term reward (e.g., "getting high"). Nonetheless, data to support the beneficial effects of cannabis use in psychiatric populations are limited, and potential harms in patients with psychotic and mood disorders have been increasingly documented. This article reviews the effects of cannabis in people with mental illness. Then, we provide a reconciliation of the addiction vulnerability and allostatic hypotheses to explain co-morbidity addiction in mentally ill cannabis users, as well as to further aid in developing a rational framework for the assessment and treatment of problematic cannabis use in these patients.

Anxiety and depression associated with tyrosine kinase inhibitor discontinuation in patients with chronic myeloid leukemia.

BACKGROUND: ABL tyrosine kinase inhibitors (TKIs) significantly changed the prognosis of patients with chronic myeloid leukemia (CML), and clinical trials demonstrated that TKIs can be discontinued in approximately 50% of patients after a period of deep molecular response (DMR). However, in some patients, TKI discontinuation leads to anxiety and depression. Here, we analysed the incidence of anxiety and depression in patients who stop TKI therapy. METHODS: Anxiety and depression were evaluated using the Hospital Anxiety and Depression Scale (HADS) in 32 patients with CML. The survey periods were at TKI discontinuation, at 1, 6, 12, and 24 months and at reintroduction of TKIs. The HADS score at the initial TKI discontinuation was compared between patients within and outside clinical trials. Treatment-free remission (TFR) rates outside clinical trials were evaluated. RESULTS: The HADS scores were significantly higher at TKI reintroduction after molecular relapse than at the initial TKI discontinuation (at the initiation of stopping TKIs vs. at reintroduction of TKIs, 8.47 ± 5.53 vs. 1.67 ± 2.26; p = 0.0003). The TFR rate at 12 months after stopping TKIs outside clinical trials was 55.6%. The HADS score at the initial TKI discontinuation did not differ between patients within and outside clinical trials. CONCLUSION: Stopping TKIs outside clinical trials is feasible if the guidelines for stopping are followed and an adequate monitoring system is available. Discontinuation of TKIs requires adequate management of anxiety and depression.