Dose-dependent opposite effects of nortriptyline on affective-like behavior in adolescent rats: Comparison with adult rats.

Antidepressant drugs elicit different behavioral and neurochemical responses with age. In fact, the use of antidepressants during adolescence is associated with an increased risk of suicidal thinking, being the best pharmacological treatment during this critical period a matter of constant debate in terms of its risk-benefit outcome. In this regard, the present study compared the effects of nortriptyline (3-10 mg/kg, 7 days) on regulating different aspects of affective-like behavior by screening adolescent and adult Sprague-Dawley rats through several consecutive tests (forced-swim, open field, sucrose preference). Brains were later collected to evaluate hippocampal neurogenesis and mBDNF protein content as potential molecular correlates of the observed behavioral responses. The main results in adolescent rats showed that nortriptyline induced dose-dependent opposite effects: while 3 mg/kg decreased immobility and increased mBDNF (indicative of an antidepressant-like response), 10 mg/kg decreased exploratory time in the open field and mBDNF (suggestive of an anxiogenic-like response). These effects were not associated with changes in neurogenesis regulation. In adult rats, nortriptyline failed to modulate affective-like behavior or the neuroplasticity markers evaluated at the doses tested. In conclusion, clear behavioral and neurochemical differences were observed between adolescent and adult rats in response to nortriptyline treatment. Interestingly, while nortriptyline displayed an antidepressant-like potential at the lowest dose examined in adolescence, a higher dose shifted these results towards a negative outcome, thus reinforcing the need to extreme caution when considering this treatment for our younger population.

A comparative study of propofol alone and propofol combined with midazolam for dental treatments in special needs patients.

ABSTRACT: Although dental treatment with sedation is performed increasingly in special needs patients, data on adding midazolam to intravenous propofol sedation are very limited for this group. The purpose of this study was to identify the factors and procedure time associated with the use of intravenous sedation with propofol alone or propofol combined with midazolam in dental patients with special needs.This was a retrospective data analysis. The sedation medications and relevant covariates, including demographic parameters, disability levels, oral health conditions, dental procedures, treatment time, and side effects, of 718 patients with special needs were collected between April 2013 and September 2014. The unfavorable side effects by sedation types were reported. Factors associated with procedure time and the sedation medications were assessed with multiple logistic regression analyses.Of 718 patients, 8 patients experienced unfavorable side effects (vomiting, sleepiness, or emotional disturbance) after the dental procedures; the rate was 0.6% in the 509 patients who received propofol only. In 209 patients who received propofol and midazolam, 2.4% experienced the side effects. Sedation time was associated with body mass index (BMI) < 25 (adjusted odds ratio [aOR] = 1.45, 95% confidence interval [CI]: 1.04-2.04) and the performance of multiple dental procedures (aOR = 1.44, 95% CI: 1.06-1.97) but not associated with the sedation types. A significant odds ratio for the combined use of propofol and midazolam was shown for adolescents (aOR = 2.22, 95% CI: 1.28-3.86), men (aOR = 2.05, 95% CI: 1.41-2.98), patients with cognitive impairment (aOR = 1.99, 95% CI: 1.21-3.29), and patients undergoing scaling procedures (aOR = 1.64, 95% CI: 1.13-2.39).With the acceptable side effects of the use of propofol alone and propofol combined with midazolam, multiple dental procedures increase the sedation time and the factors associated with the combined use of propofol and midazolam are younger age, male sex, recognition problems, and the type dental procedure in the dental treatment of patients with special needs.

Evaluation of Emotional Adverse Effects of Antidepressants: A Follow-up Study.

PURPOSE/BACKGROUND: Emotional adverse effects due to antidepressant use may cause difficulties for the clinician in the treatment of depression. In this prospective study, the emotional adverse effects of antidepressants were evaluated in various aspects. METHODS/PROCEDURES: Ninety eight patients diagnosed with major depressive disorder were included in the study. At 2nd, 4th, 8th, 12th, and 16th weeks, patients were assessed with Montgomery-Asberg Depression Rating Scale (MADRS), and the antidepressant dose was increased in patients with less than a 50% reduction at each visit compared with the initial MADRS score. The Oxford Questionnaire on the Emotional Side-effects of Antidepressants (OQESA) was used at the 8th-week and 16th-week visits. FINDINGS/RESULTS: A significant difference is found in the OQESA score at the 8th-week visit compared with the 16th-week assessment (P < 0.001, t = 5.73). There were significant correlations between MADRS scores and OQESA scores both at the 8th (r = 0.346, P = 0.05) and the 16th (r = 0.490, P < 0.001) weeks. In regression analyses, at eighth-week assessment, MADRS score (B = 1.487, P = 0.002) and selective serotonin reuptake inhibitor use (B = 14.014, P = 0.023) had a significantly predicted OQESA score. IMPLICATIONS/CONCLUSIONS: In this study, it is found that, as the rate of remitted patients is increased, OQESA scores get decreased, and furthermore, the OQESA score of the remitted group is statistically low when compared with that of the nonremitted group at the 8th- and 16th-week visits. Oxford Questionnaire on the Emotional Side-effects of Antidepressants and MADRS scores are significantly correlated in all assessments. These results suggest that the score obtained from OQESA may be related not only to the emotional adverse effects of antidepressants but also to the residual symptoms of depression.

Efeitos adversos associados a uso de contraceptivos orais em discentes / Adverse effects associated with students' use of oral contraceptives

Objetivos: Investigar o número de mulheres, as causas que levam a fazer o uso e descrever os efeitos adversos mais comuns associados ao uso de contraceptivos orais de forma contínua. Métodos: Trata-se de estudo observacional, transversal ou de prevalência e quantitativo. A pesquisa teve população de 832 alunas do curso de Direito dos turnos matutino, vespertino e noturno, no período de agosto a setembro, tendo como amostra 248 participantes para esse estudo. O questionário versou sobre o uso de anticoncepcionais, o perfil das usuárias e os possíveis efeitos adversos observados ao longo do uso. Resultados: A prevalência de uso dos contraceptivos orais foi de 42,3%, justificada principalmente pelo desejo de evitar a concepção (42,9%), regular os níveis hormonais (25,7%) e tratar acne (15,2%). Cerca de 63,8% relataram que já sentiram algum desconforto associado ao uso destes medicamentos, sendo os mais frequentes aumento de peso corporal (32,4%), alterações de humor (24,3%), dor nas mamas (13,5%), cefaleia (4,1%), dor abdominal (2,7%). Conclusão: A prevalência de efeitos adversos decorrentes do uso contínuo de contraceptivos orais é alta, evidenciando-se a necessidade de conscientizar as usuárias a buscarem profissionais habilitados, para que elas façam uso do anticoncepcional mais adequado, minimizando o desconforto advindo dos efeitos adversos.

Objectives: To investigate the number of women, the causes that lead to making use, and to describe the most common adverse effects associated with oral contraceptive continuous use. Methods: This is an observational, cross-sectional, or prevalence and quantitative study. The research had a population of 832 students of the law course of the morning, afternoon and evening shifts, from August to September, with a sample of 248 participants for this study. The questionnaire was about contraceptive use, users' profile, and possible adverse effects observed during use. Results: The prevalence of oral contraceptive use was 42.3%, mainly explained by the desire to avoid conception (42.9%), regulate hormone levels (25.7%), and to treat acne (15.2%). About 63.8% reported already having some discomfort associated with the use of these medications, with the most frequent being body weight gain (32.4%), mood swings (24.3%), breast pain (13.5%), headache (4.1%), abdominal pain (2.7%). Conclusion: The prevalence of adverse effects resulting from the continued use of oral contraceptives is high, so there is a need to guide users to seek qualified professionals so that they make use of the most appropriate contraceptive, minimizing the discomfort arising from adverse effects.

Role of the endocannabinoid and endovanilloid systems in an animal model of schizophrenia-related emotional processing/cognitive deficit.

Studies suggest that the endocannabinoid and endovanilloid systems are implicated in the pathophysiology of schizophrenia. The Spontaneously Hypertensive Rats (SHR) strain displays impaired contextual fear conditioning (CFC) attenuated by antipsychotic drugs and worsened by pro-psychotic manipulations. Therefore, SHR strain is used to study emotional processing/associative learning impairments associated with schizophrenia and effects of potential antipsychotic drugs. Here, we evaluated the expression of CB1 and TRPV1 receptors in some brain regions related to the pathophysiology of schizophrenia. We also assessed the effects of drugs that act on the endocannabinoid/endovanilloid systems on the CFC task in SHRs and control animals (Wistar rats - WRs). The following drugs were used: AM404 (anandamide uptake/metabolism inhibitor), WIN55-212,2 (non-selective CB1 agonist), capsaicin (TRPV1 agonist), and capsazepine (TRPV1 antagonist). SHRs displayed increased CB1 expression in prelimbic cortex and cingulate cortex area 1 and in CA3 region of the dorsal hippocampus. Conversely, SHRs exhibited decreases in TRPV1 expression in prelimbic and CA1 region of dorsal hippocampus and increases in the basolateral amygdala. AM404, WIN 55,212-2 and capsaicin attenuated SHRs CFC deficit, although WIN 55,212-2 worsened SHRs CFC deficit in higher doses. WRs and SHRs CFC were modulated by distinct doses, suggesting that these strains display different responsiveness to cannabinoid and vanilloid drugs. Treatment with capsazepine did not modify CFC in either strains. The effects of AM404 on SHRs CFC deficit was not blocked by pretreatment with rimonabant (CB1 antagonist) or capsazepine. These results reinforce the involvement of the endocannabinoid/endovanilloid systems in the SHRs CFC deficit and point to these systems as targets to treat the emotional processing/cognitive symptoms of schizophrenia.

Prenatal exposure to non-steroidal anti-inflammatory drugs (NSAIDs) and neurodevelopmental outcomes in children.

PURPOSE: Non-steroidal anti-inflammatory drugs (NSAIDs) are commonly used during pregnancy. Findings that prenatal NSAID exposure may affect offspring neurodevelopment have been inconsistent. We investigated the effect of prenatal NSAID exposure on childhood neurodevelopment and explored the susceptibility of our effect estimates to forms of bias via negative exposure, negative outcome, and multi-informant analyses. METHODS: In a cohort of pregnant women (n = 6876), perinatal NSAID use was assessed by prescriptions and self-report. Primary neurodevelopmental outcomes included attention problems using maternal reports at 1½, 3, and 5 years. To explore potential systematic biases, we compared estimates from maternally reported attention problems to a teacher's report and a measure of nonverbal intelligence assessed at a clinic visit at age 6 years; we also used NSAID use before pregnancy and somatic problems as a "negative" exposure and outcome, respectively. RESULTS: Maternal reports suggested that prenatal exposure to NSAIDs was associated with more attention problems at younger ages (eg, at age 3: mean difference in attention problems score: 0.30; 95% CI 0.12, 0.48). However, no strong association with attention problems was found in the teacher report, and a similarly strong association between prenatal NSAID exposure and somatic complaints suggests residual confounding by indication likely remains. Moreover, prenatal exposure to NSAIDs was not associated with an observed measure of IQ (mean difference in IQ score: -0.32; 95% CI: -1.82, 1.19). CONCLUSIONS: Jointly, our results suggest that the observed associations between prenatal exposure to NSAIDs and child attention problems reflect systematic biases of a null or small effect.

The association between polypharmacy and late life deficits in cognitive, physical and emotional capability: a cohort study.

Background Polypharmacy is a growing health concern for older adults and is associated with poorer clinical outcome. Objective This study aim is to investigate the association between polypharmacy and impairment in cognitive, physical and emotional capability controlling for the confounding effect of co-morbidities. Setting The Aberdeen 1936 Birth Cohort from 1999 to 2004. Method Recruited were 498 dementia free participants around 64 years old and recruited into wave one. Linear regression and structural equation models were used. Models were adjusted for the effect of age, gender, childhood IQ, education and Body Mass Index. A triad of impairment was defined as a composite measure of impairment in cognitive, physical and emotional function. Main outcome measure The relationships between polypharmacy, co-morbidity and triad of impairment. Results The prevalence of polypharmacy was 12.3% in this relatively healthy sample. Polypharmacy was significantly associated with increased impairment in cognitive, physical and emotional ability (ß = 3.6, p = 0.003) after controlling for the effect of comorbidities and other confounding variables. As expected, higher childhood IQ and educational achievement had protective effects against impairment while higher comorbidity score and Body Mass Index were associated with increased impairment in this population. Conclusions The independent association of polypharmacy and reduced cognitive, physical and emotional capability makes this a promising target for predicting and potentially reducing the risk of impairment and associated healthcare costs in older adults. Longitudinal studies are required to investigate the underlying mechanisms for the observed relationships further.

Cognitive and emotional impairments after cutaneous intoxication by CEES (a sulfur mustard analog) in mice.

Cognitive and emotional disorders have been reported in veterans intoxicated with sulfur mustard (SM) a chemical weapon belonging to the category of vesicating agents. However, the intense stress associated with the SM intoxication may render difficult determining the exact role played by SM intoxication itself on the emergence and maintaining of cognitive disorders. Animal's model would allow overcoming this issue. So far, we presently investigated the cognitive and emotional impact of an acute cutaneous intoxication with CEES (2-chloroethyl ethyl sulfide), a SM analog in C57/Bl6 mice. Our study evidenced that up to 5days after a single acute neat CEES skin exposure, compared to controls, mice exhibited i) a significant increase in anxiety-like reactivity in an elevated plus-maze and in an open-field tasks and ii) an alteration of working memory in a sequential alternation task. In contrast, mice submitted to intoxication with a diluted CEES solution or hydrochloric acid (HCl) did not show any memory or emotional impairments. Given that, Our data shows that a single local cutaneous intoxication with neat CEES induced long-lasting cognitive and emotional pejorative effects, in accordance with the epidemiological observations in veterans. Thus, the single acute neat CEES cutaneous intoxication in mice could allow studying the sulfur mustard-induced cognitive and emotional disorders and their further counter-measures.

Emotional and motor symptoms in riverside dwellers exposed to mercury in the Amazon. / Manifestações emocionais e motoras de ribeirinhos expostos ao mercúrio na Amazônia.

INTRODUCTION:: The investigation of clinical and neurological impactations associated with exposure to mercury levels in exposed populations is necessary in the Amazon. OBJECTIVE:: To analyze emotional and motor symptoms of riverside dwellers exposed by diet in the municipalities of Itaituba and Acará, in Pará, Brazil. METHODS:: Hair samples were collected to assess the total mercury (HgT). Demographic data as well as emotional (depression, anxiety and insomnia) and motor (paresthesia, muscle weakness, loss of balance when walking, tremors, limb pain and dysarthria) symptomatology data were obtained. RESULTS:: Mean levels of HgT in Itaituba were significantly higher (p < 0.0001) than in Acará. Emotional symptoms were identified in 26 (26.5%) participants from Itaituba and in 24 (52.2%) from Acará. Specific motor complaints in Itaituba occurred in 63 (64.3%) volunteers; the most frequently mentioned afflictions were limb pain (36.7%), paresthesia (32.6%) and muscle weakness (27.5%). In Acará, 33 (71.7%) participants had motor symptoms, the majority of which complained of paresthesia (54.3%), limb pain (52.2%) and tremors (34.8%). Average HgT levels in Itaituba in those with emotional and motor symptoms were above the tolerable levels (6 µg/g) determined by the World Health Organization. CONCLUSION:: Results showed that mercury levels in emotional and motor symptoms in Itaituba are higher than in riverside dwellers in Acará. Further studies, including the application of specific qualitative and/or quantitative standard tests, as well as the investigation of other clinical signs are necessary.

Emotional blunting with antidepressant treatments: A survey among depressed patients.

BACKGROUND: Emotional blunting is regularly reported in depressed patients on antidepressant treatment but its actual frequency is poorly understood. We have previously used qualitative methods to develop an appropriate scale, the Oxford Questionnaire on the Emotional Side-Effects of Antidepressants (OQESA). METHODS RESULTS: Six hundred and sixty nine depressed patients on treatment and 150 recovered (formerly depressed) controls (aged ≥18 years) participated in this internet-based survey. The rate of emotional blunting in treated depressed patients was 46%, slightly more frequent in men than women (52% versus 44%) and in those with higher Hospital Anxiety and Depression (HAD) scale scores. There was no difference according to antidepressant agent, though it appeared less frequent with bupropion. Depressed patients with emotional blunting had much higher total blunting scores on OQESA than controls (42.83 ± 14.73 versus 25.73 ± 15.00, p < 0.0001) and there was a correlation between total blunting score and HAD-Depression score (r = 0.521). Thus, those with HAD-D score >7 (n = 170) had a higher total questionnaire score, 49.23±12.03, than those with HAD-D score ≤7 (n = 140), 35.07 ± 13.98, and the difference between the two groups was highly significant. However, patients with HAD-D score ≤7 (n = 140) had a higher total score (35.07 ± 13.98) than the recovered controls (n = 150) (25.73 ± 15.00), and the difference between the two groups was significant. Among the patients with emotional blunting, 37% had a negative perception of their condition and 38% positive. Men reported a more negative perception than women (p=0.008), and patients with a negative perception were more likely to have higher HAD scores. Higher levels of emotional blunting are associated with a more negative perception of it by the patient (r = -0.423). LIMITATIONS: Include self-evaluation and the modest size of the sample for detection of differences between antidepressants. CONCLUSIONS: Emotional blunting is reported by nearly half of depressed patients on antidepressants. It appears to be common to all monoaminergic antidepressants. The OQESA scores are highly correlated with HAD depression score; emotional blunting cannot be described simply as a side-effect of antidepressants, but also as a symptom of depression. A higher degree of emotional blunting is associated with a poorer quality of remission. The OQESA scale allows the detection of this phenomenon.

Manifestações emocionais e motoras de ribeirinhos expostos ao mercúrio na Amazônia / Emotional and motor symptoms in riverside dwellers exposed to mercury in the Amazon

RESUMO: Introdução: A investigação dos impactos clínico-neurológicos associados às concentrações de exposição ao mercúrio em populações expostas é necessária na Amazônia. Objetivo: Analisar as manifestações emocionais e motoras de ribeirinhos expostos pela dieta nos municípios de Itaituba e Acará, ambos no Pará. Método: Foram coletadas amostras de cabelo para a determinação de mercúrio total (HgT), obtidos dados demográficos e sintomatológicos emocionais (depressão, ansiedade e insônia) e motores (parestesia, fraqueza muscular, desequilíbrio ao andar, tremor, dor nos membros e disartria). Resultados: A concentração mediana de HgT em Itaituba foi significativamente superior (p < 0,0001) àquela em Acará. As manifestações emocionais foram identificadas em 26 (26,5%) participantes de Itaituba e em 24 (52,2%) em Acará. Com relação às queixas motoras especificas, em Itaituba ocorreram em 63 (64,3%) voluntários, sendo mais referidas a dor nos membros (36,7%), a parestesia (32,6%) e a fraqueza muscular (27,5%). No Acará, 33 (71,7%) participantes apresentaram manifestações motoras, com o maior número queixando de parestesia (54,3%), dor nos membros (52,2%) e tremor (34,8%). As concentrações médias de HgT em Itaituba naqueles com manifestações emocionais e com manifestações motoras estiveram acima do considerado tolerável (6 µg/g) pela Organização Mundial de Saúde. Conclusão: Os resultados revelaram que a concentração de mercúrio nas manifestações emocionais e motoras de Itaituba são maiores do que nos ribeirinhos do Acará. Novos estudos são necessários com a aplicação de testes convencionais qualitativos e/ou quantitativos específicos, assim como também a investigação de outros sinais clínicos.

ABSTRACT: Introduction: The investigation of clinical and neurological impactations associated with exposure to mercury levels in exposed populations is necessary in the Amazon. Objective: To analyze emotional and motor symptoms of riverside dwellers exposed by diet in the municipalities of Itaituba and Acará, in Pará, Brazil. Methods: Hair samples were collected to assess the total mercury (HgT). Demographic data as well as emotional (depression, anxiety and insomnia) and motor (paresthesia, muscle weakness, loss of balance when walking, tremors, limb pain and dysarthria) symptomatology data were obtained. Results: Mean levels of HgT in Itaituba were significantly higher (p < 0.0001) than in Acará. Emotional symptoms were identified in 26 (26.5%) participants from Itaituba and in 24 (52.2%) from Acará. Specific motor complaints in Itaituba occurred in 63 (64.3%) volunteers; the most frequently mentioned afflictions were limb pain (36.7%), paresthesia (32.6%) and muscle weakness (27.5%). In Acará, 33 (71.7%) participants had motor symptoms, the majority of which complained of paresthesia (54.3%), limb pain (52.2%) and tremors (34.8%). Average HgT levels in Itaituba in those with emotional and motor symptoms were above the tolerable levels (6 µg/g) determined by the World Health Organization. Conclusion: Results showed that mercury levels in emotional and motor symptoms in Itaituba are higher than in riverside dwellers in Acará. Further studies, including the application of specific qualitative and/or quantitative standard tests, as well as the investigation of other clinical signs are necessary.

Adverse effects and treatment satisfaction among online users of four antidepressants.

Adverse effects (AEs) are an important factor in antidepressant treatment decision-making, though common AE profiles from clinical trial research highlight physical AEs to the neglect of emotional and behavioral AEs. First-hand accounts of antidepressant users on the Internet can supplement AE profiles with information gained from real-world treatment experiences. We examined online user reviews of two older (escitalopram; duloxetine) and two newer (vilazodone; vortioxetine) antidepressants for differences in their AE profiles and determined which categories of AEs were associated with users' satisfaction. A codebook of 60 physical, emotional, and behavioral AEs was used for line-by-line coding of effects reported among 3243 user reviews from three popular health websites. Emotional and behavioral effects were commonly reported (41%), followed by sleep (31.9%) and gastrointestinal (25.0%) effects. Specific AEs statistically significantly varied across drugs, creating potentially meaningful differences in AE profiles. Users of newer drugs more often reported emotional instability, while users of older drugs reported more emotional blunting. Emotional and behavioral AEs demonstrated moderate to substantial relationships with users' satisfaction, whereas gastrointestinal, metabolic, or sexual AEs were minimally related. More specific and systematic assessment of a broader range of AEs is needed in both research and practice.

Considering benefits and harms of duloxetine for treatment of stress urinary incontinence: a meta-analysis of clinical study reports.

BACKGROUND: The European Medicines Agency makes clinical study reports publicly available and publishes reasons for not approving applications for marketing authorization. Duloxetine has been approved in Europe for the treatment of stress urinary incontinence in women. The reported adverse effects of duloxetine include mental health problems and suicidality. We obtained clinical study reports from the European Medicines Agency concerning use of this drug for stress urinary incontinence. METHODS: We performed a meta-analysis of 4 randomized placebo-controlled trials of duloxetine (involving a total of 1913 patients) submitted to the European Medicines Agency for marketing approval for the indication of stress urinary incontinence in women. We used data from the clinical study reports (totalling 6870 pages and including individual patient data) to assess benefits (including frequency of incontinence and changes in quality-of-life scores, such as Patient Global Impression of Improvement rating) and harms (both general harms, including discontinuation because of adverse events, and harms related to suicidality, violent behaviour and their potential precursors, such as akathisia and activation [stimulating effects such as insomnia, anxiety and agitation]). RESULTS: Duloxetine was significantly better than placebo in terms of percentage change in weekly incontinence episodes (mean difference -13.56%, 95% confidence interval [CI] -21.59% to -5.53%) and change in Incontinence Quality of Life total score (mean difference 3.24, 95% CI 2.00 to 4.48). However, the effect sizes were small, and a sensitivity analysis (with removal of one trial) showed that the number needed to treat for a Patient Global Impression of Improvement rating of "much better or very much better" was 8 (95% CI 6 to 13). The numbers needed to harm were 7 (95% CI 6 to 8) for discontinuing because of an adverse event and 7 (95% CI 6 to 9) for experiencing an activation event. No suicidality, violence or akathisia events were noted. INTERPRETATION: Although duloxetine is effective for stress urinary incontinence in women, the rates of associated harm were high when individual patient data were analyzed, and the harms outweighed the benefits.

Evidence for the Risks and Consequences of Adolescent Cannabis Exposure.

OBJECTIVE: This review of the scientific literature examines the potential adult sequelae of exposure to cannabis and related synthetic cannabinoids in adolescence. We examine the four neuropsychiatric outcomes that are likely most vulnerable to alteration by early cannabinoid use, as identified within both the clinical and preclinical research: cognition, emotional functioning, risk for psychosis, and addiction. METHOD: A literature search was conducted through PubMed, PsychInfo, and Google Scholar with no publication date restrictions. The search terms used were "adolescent" and "adult," and either "cannabis," "marijuana," "delta-9-tetra-hydrocannabinol," or "cannabinoid," which was then crossed with one or more of the following terms: "deficit," "impairment," "alteration," "long-term," "persistent," "development," "maturation," and "pubescent." RESULTS: The majority of the clinical and preclinical data point to a strong correlation between adolescent cannabinoid exposure and persistent, adverse neuropsychiatric outcomes in adulthood. Although the literature supports the hypothesis that adolescent cannabis use is connected to impaired cognition and mental health in adults, it does not conclusively demonstrate that cannabis consumption alone is sufficient to cause these deficits in humans. The animal literature, however, clearly indicates that adolescent-onset exposure to cannabinoids can catalyze molecular processes that lead to persistent functional deficits in adulthood, deficits that are not found to follow adult-onset exposure and that model some of the adverse outcomes reported in humans among adult populations of early-onset cannabis users. CONCLUSION: Based on the data in the current literature, a strong association is found between early, frequent, and heavy adolescent cannabis exposure and poor cognitive and psychiatric outcomes in adulthood, yet definite conclusions cannot yet be made as to whether cannabis use alone has a negative impact on the human adolescent brain. Future research will require animal models and longitudinal studies to be carefully designed with a focus on integrating assessments of molecular, structural, and behavioral outcomes in order to elucidate the full range of potential adverse and long-term consequences of cannabinoid exposure in adolescence.

Thimerosal exposure and disturbance of emotions specific to childhood and adolescence: A case-control study in the Vaccine Safety Datalink (VSD) database.

BACKGROUND: This study evaluated Thimerosal-containing childhood vaccines and the risk of a diagnosis called disturbance of emotions specific to childhood and adolescence (ED). Thimerosal is an organic-mercury (Hg)-containing compound used in some vaccines. METHODS: A hypothesis-testing prospective, longitudinal case-control study evaluated Hg exposure from Thimerosal in hepatitis B vaccines administered at specific times within the first 6 months of life and its association with medically diagnosed ED (313.xx) (n = 517) in children born between 1991-2000 in comparison to controls (n = 27 491) in the Vaccine Safety Datalink (VSD) database. RESULTS: Cases diagnosed with ED were significantly more likely than controls to have received increased Hg exposure within the first month of life (odds ratio (OR) = 1.3384), the first 2 months of life (OR = 1.3367) and the first 6 months of life (OR = 2.37). When the data were separated by gender, similar significant adverse effects were observed for males, but not females. On a per microgram Hg basis, cases diagnosed with ED were significantly more likely than controls to have received increased exposure within the first 6 months of life (OR = 1.025 per microgram Hg). CONCLUSIONS: The results show a significant relationship between Hg exposure from Thimerosal-containing childhood vaccines and the subsequent risk of an ED diagnosis.

Dexmedetomidine use in the ED for control of methamphetamine-induced agitation.

BACKGROUND: Chemical restraint is often required to control agitation induced by methamphetamine. Dexmedetomidine is an α-2 adrenergic receptor agonist with sedative, analgesic, and sympatholytic properties. Its use in the emergency department (ED) to control methamphetamine-induced agitation has not been reported. OBJECTIVE: To report two cases of methamphetamine-induced agitation successfully sedated with dexmedetomidine in the ED. CASE REPORT: The first case was a 42-year-old man with unstable emotion and violent behaviours after smoking methamphetamine. His agitation did not respond to a large cumulative dose of benzodiazepines (10mg of diazepam and 332mg of midazolam) administered over 48h and sedation was achieved with dexmedetomidine. The second case was a 38-year-old methamphetamine user with unstable emotion and recurrent episodes of agitation despite repeated doses of benzodiazepines, whose agitation was controlled with dexmedetomidine infusion. DISCUSSION: In both cases, dexmedetomidine apparently reduced the dose of benzodiazepines needed to achieve adequate sedation. Transient falls in blood pressure and slowing of the heart rate were noted, which resolved either spontaneously or after reducing the infusion rate without requiring drug treatment. CONCLUSION: Dexmedetomidine can be considered as an adjunct for chemical restraint when standard treatment fails to control the agitation induced by methamphetamine, but patient's hemodynamic state should be monitored closely during administration. Its efficacy and safety in the ED warrant further evaluation with prospective controlled trials.

Combined oral contraceptive use is associated with both improvement and worsening of mood in the different phases of the treatment cycle-A double-blind, placebo-controlled randomized trial.

OBJECTIVE: Ever since the introduction of combined oral contraception (COC), one of the major reasons for discontinuing the pill use has been mood-related side effects. Moreover, women who discontinue the pill turn to less effective methods whereby the probability of an unintended conception increases. Approximately 4-10% of COC users complain of depressed mood, irritability or increased anxiety, but drug-related causality has been difficult to prove. Given the lack of randomized controlled trials in this area, we aimed to prospectively estimate the severity of adverse mood in COC users that would be as representative of general users as possible. METHODS: This investigator-initiated, multi-center, randomized, double-blinded, placebo-controlled study included 202 healthy women. Women were randomized to a COC (1.5mg estradiol and 2.5mg nomegestrolacetate) or placebo for three treatment cycles. Main outcome measure was the Daily Record of Severity of Problems (DRSP), which was filled out daily during one baseline cycle and the final treatment cycle. RESULTS: Results from 84 women in the COC group and 94 women in the placebo group were analysed. COC use was associated with small, but statistically significant, increases in mean anxiety (0.22; 95% CI: 0.07-0.37, p=0.003), irritability (0.23; 95% CI: 0.07-0.38, p=0.012), and mood swings scores (0.15; 95% CI: 0.00-0.31, p=0.047) during the intermenstrual phase, but a significant premenstrual improvement in depression (-0.33; 95% CI: -0.62 to -0.05, p=0.049). Secondary analyses showed that women with previous adverse hormonal contraceptive experience reported significantly greater mood worsening in the intermenstrual phase in comparison with healthy women, p<0.05. The proportion of women who reported a clinically relevant mood deterioration did not differ between those allocated to COC (24.1%) or placebo (17.0%), p=0.262. CONCLUSION: COC use is associated with small but statistically significant mood side effects in the intermenstrual phase. These findings are driven by a subgroup of women who clearly suffer from COC-related side effects. However, positive mood effects are noted in the premenstrual phase and the proportion of women with clinically relevant mood worsening did not differ between treatment groups.

RETRACTED: Evaluation of behavioral problems after prenatal dexamethasone treatment in Swedish adolescents at risk of CAH.

This article has been retracted: please see Elsevier Policy on Article Withdrawal (http://www.elsevier.com/locate/withdrawalpolicy). This article has been retracted at the request of the authors due to technical errors that have called into question the reliability of the data used to inform the author's conclusions. All data on cognitive and behavioral outcomes in CAH and non­CAH cases, treated or not treated with DEX prenatally, were put into a single Excel database. The authors had in total four different patient groups for each age group (5­6 y, 7­17 y and 18-35 y). The database consisted of 237 cases in total and there were multiple columns for the different outcome measures. When the behavioral data for the sub-cohort described in this paper (first trimester treated non-CAH cases and healthy population controls, age 7­17 y) were copied to another sheet and compressed/modified in preparation for statistical analysis in SPSS, an error occurred. This technological issue caused rows to shift and the data from the different groups got mixed up. In particular, the non­CAH group versus the control group were "contaminated" with cases from the wrong patient group. The authors discovered this mistake when they started to analyse the data from the other sub­groups of patients, the CAH cases and the adult cohort, which was after their original results had already been published in Hormones and Behavior in this manuscript "Evaluation of behavioral problems after prenatal dexamethasone treatment in Swedish adolescents at risk of CAH". It then became apparent that the entire data set was unreliable and needed to be re­analysed which is what has motivated the retraction of this article. The authors have recently completed this re­analysis and the results have been published here: https://www.sciencedirect.com/science/article/pii/S0018506X17300752

Mood disturbance during experimental endotoxemia: Predictors of state anxiety as a psychological component of sickness behavior.

Lipopolysaccharide (LPS) administration is a well-established model to assess afferent immune-to-brain communication and behavioral aspects of inflammation. Nevertheless, only few studies in comparatively small samples have assessed state anxiety as a psychological component of sickness behavior despite possible clinical implications for the pathophysiology of neuropsychiatric conditions. Thus, the goal of the present analyses carried out in a large, pooled dataset from two independent study sites was to analyze the state anxiety response to LPS administration and to investigate predictors (i.e., cytokine changes; pre-existing anxiety and depression symptoms assessed with the Hospital Anxiety and Depression Scale) of the LPS-induced state anxiety changes at different time points after LPS administration. Data from 186 healthy volunteers who participated in one of six randomized, placebo-controlled human studies involving intravenous administration of LPS at doses of 0.4-0.8ng/kg body weight were combined. State anxiety as well as circulating interleukin (IL)-6, tumor necrosis factor (TNF)-α and IL-10 concentrations were significantly increased 2h and 3h after LPS administration, with a peak at 2h, and returned to baseline 6h after administration. Greater changes in IL-6 from baseline to 3h after LPS administration significantly and independently predicted a more pronounced LPS-induced state anxiety response. In addition, higher pre-existing subclinical anxiety symptoms significantly predicted a lower increase in state anxiety 3h and 6h after LPS-administration, which was mediated by TNF-α changes. In conclusion, our findings give additional support for a putative role of inflammatory mechanisms in the pathophysiology of stress-related and anxiety disorders and give new insight on the potential role of pre-existing subclinical affective symptoms.