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Objective: This is a feasibility study evaluating the safety, tolerability, and potential anxiolytic efficacy of the α2 agonist guanfacine extended-release (GXR) in children and adolescents with generalized anxiety disorder (GAD), separation anxiety disorder (SAD), or social phobia/social anxiety disorder. Methods: Youth aged 6–17 years with a primary diagnosis of GAD, SAD, and/or social anxiety disorder were treated with flexibly dosed GXR (1–6 mg daily, n = 62) or placebo (n = 21) for 12 weeks. The primary aim of this study was to determine the safety and tolerability of GXR in youth with anxiety disorders, which involved the analysis of treatment-emergent adverse events (TEAEs), the emergence of suicidal ideation and behaviors, vital signs, and electrocardiographic/laboratory parameters. Exploratory efficacy measures included dimensional anxiety scales (Pediatric Anxiety Rating Scale [PARS] and Screen for Child Anxiety Related Emotional Disorders [SCARED]), as well as the Clinical Global Impression–Improvement (CGI-I) scale. As this was an exploratory study, no inferential statistical analyses were performed. Results: GXR was safe and well tolerated. Treatment-related mean ± standard deviation changes in heart rate (GXR: 1.8 ± 12 beats per minute [bpm] decrease; placebo: 0.5 ± 11 bpm decrease), systolic blood pressure (GXR: 2.3 ± 11 mm Hg decrease; placebo: 1.7 ± 11 mm Hg decrease), or diastolic blood pressure (GXR: 1.3 ± 9 mm Hg decrease; placebo: 0.9 ± 7 mm Hg increase) were similar between treatment groups. TEAEs, including headache, somnolence/fatigue, abdominal pain, and dizziness, were consistent with the known safety profile of GXR. No differences were observed between treatment groups for PARS and SCARED scores, although at endpoint, a higher proportion of subjects receiving GXR versus placebo demonstrated CGI-I scores ≤2 (54.2% vs. 31.6%), as rated by the clinician investigator. Conclusions: GXR was well tolerated in pediatric subjects with GAD, SAD, and/or social anxiety disorder. ClinicalTrials.gov Identifier: NCT01470469.

Background Separation anxiety disorder was recently recognized by fifth edition of the Diagnostic and Statistical Manual of Mental Disorders as a diagnosis in adults, but no publications to date have characterized a sample of patients seeking treatment for adult separation anxiety disorder (ASAD) or assessed treatment efficacy. We hypothesized that vilazodone, a selective serotonin reuptake inhibitor (SSRI) and serotonin 1a (5HT1a) receptor partial agonist, would have efficacy in ASAD, because SSRIs have appeared efficacious in children with mixed diagnoses including separation anxiety disorder and in animal models of separation anxiety. Methods In this pilot study, 24 adults (ages 18–60) with a principal diagnosis of ASAD were randomized to 12 weeks of double‐blind treatment with vilazodone (n = 13) or placebo (n = 11). Outcome was assessed by an independent evaluator and self‐ratings, and analyzed with mixed effect models. Results This sample was predominantly female (67%), with comorbid psychiatric disorders (58%), and adult onset of separation anxiety disorder (62%). Response rates at week 12 did not differ significantly between groups. Across all time points, the vilazodone group evidenced greater improvement on the Structured Clinical Interview for Separation Anxiety Symptoms (P = .026) and the Quality of Life Enjoyment and Satisfaction Questionnaire (P = .011), and trends toward greater improvement on the Adult Separation Anxiety Questionnaire (P = .054) and the Clinical Global Impression–Change Scale (P = .086), all with large between‐group effect sizes. Conclusions Findings demonstrate feasibility of a clinical trial in ASAD, and they suggest that vilazodone may have efficacy in the treatment of ASAD and warrants further study.

The endocannabinoids anandamide and 2-arachidonoyglycerol (2-AG) may contribute to the regulation of mood and emotion. In this study, we investigated the impact of the endocannabinoid transport inhibitor AM404 on three rat models of anxiety: elevated plus maze, defensive withdrawal and separation-induced ultrasonic vocalizations. AM404 (1-5 mg kg(-1), intraperitoneal (i.p.)) exerted dose-dependent anxiolytic-like effects in the three models. These behavioral effects were associated with increased levels of anandamide, but not 2-AG, in the prefrontal cortex and were prevented by the CB(1) cannabinoid antagonist rimonabant (SR141716A), suggesting that they were dependent on anandamide-mediated activation of CB(1) cannabinoid receptors. We also evaluated whether AM404 might influence motivation (in the conditioned place preference (CPP) test), sensory reactivity (acoustic startle reflex) and sensorimotor gating (prepulse inhibition (PPI) of the startle reflex). In the CPP test, AM404 (1.25-10 mg kg(-1), i.p.) elicited rewarding effects in rats housed under enriched conditions, but not in rats kept in standard cages. Moreover, AM404 did not alter reactivity to sensory stimuli or cause overt perceptual distortion, as suggested by its lack of effect on startle or PPI of startle. These results support a role of anandamide in the regulation of emotion and point to the anandamide transport system as a potential target for anxiolytic drugs.

BACKGROUND: Canine separation-related problems (SRP) (also described as “separation anxiety” or “separation distress”) are among the most common behavioural complaints of dog owners. Treatment with psychoactive medication in parallel with a behaviour modification plan is well documented in the literature, but it is unknown if this is associated with an improvement in underlying affective state (emotion and mood) or simply an inhibition of the behaviour. Cognitive judgement bias tasks have been proposed as a method for assessing underlying affective state and so we used this approach to identify if any change in clinical signs during treatment was associated with a consistent change in cognitive bias (affective state). Five dogs showing signs of SRP (vocalising – e.g. barking, howling-, destruction of property, and toileting – urination or defecation- when alone) were treated with fluoxetine chewable tablets (Reconcile™) and set on a standard behaviour modification plan for two months. Questionnaires and interviews of the owners were used to monitor the clinical progress of the dogs. Subjects were also evaluated using a spatial cognitive bias test to infer changes in underlying affect prior to, and during, treatment. Concurrently, seven other dogs without signs of SRP were tested in the same way to act as controls. Furthermore, possible correlations between cognitive bias and clinical measures were also assessed for dogs with SRP. RESULTS: Prior to treatment, the dogs with SRP responded to ambiguous positions in the cognitive bias test negatively (i.e. with slower running speeds) compared to control dogs (p < 0.05). On weeks 2 and 6 of treatment, SRP dogs displayed similar responses in the cognitive bias test to control dogs, consistent with the possible normalization of affect during treatment, with this effect more pronounced at week 6 (p > 0.05). Questionnaire based clinical measures were significantly correlated among themselves and with performance in the cognitive bias test. CONCLUSION: These results demonstrate for the first time that the clinical treatment of a negative affective state and associated behaviours in a non-human species can produce a shift in cognitive bias. These findings demonstrate how the outcome of an intervention on a clinical problem can be evaluated to determine not only that the subject’s behaviour has improved, but also its psychological state (welfare)

The purpose of this study is to examine the use of prescribed psychoactive medications in a prospective cohort of children shortly after they entered foster homes; and to identify demographics, maltreatment history, psychiatric diagnoses including ADHD comorbidity, and level of aggression that contribute to prescribed use of stimulant and atypical antipsychotic medication over time. The sample included N = 252 children (nested in 95 sibling groups) followed for three years up to 4 yearly waves. Nearly all (89%) met criteria for at least one of eight psychiatric diagnoses and 31% (75/252) used one or more prescribed psychoactive medications. Over half (55%) were diagnosed with Attention Deficit Hyperactivity Disorder (ADHD); of these 38% used stimulants and 36% used atypical antipsychotics. Of the 75 medicated children, 19% received ≥3 different classes of drugs over the course of the study. Stimulants (69%) and atypical antipsychotics (65%) were the most frequently used drugs among medicated children. Adjusted odds ratios (AOR) showed that male gender (AOR = 3.2; 95% CI = 1.5-9.3), African American vs Latino ethnicity (AOR = 5.4; 95% CI = 2.1-14.2), ADHD regardless of Oppositional Defiant (ODD) or Conduct (CD) comorbidity (AOR = 6.0, 95% CI = 1.3-27.5), ODD or CD (AOR = 11.1, 95% CI = 2.1-58.6), and Separation Anxiety (AOR = 2.0, 95% CI = 1.0-4.0) psychiatric disorders were associated with the use of prescribed stimulants; while male gender (AOR = 3.8, 95% CI = 1.5-9.3), African American vs Latino (AOR = 5.1, 95% CI = 1.2-9.2) or Mixed/Other ethnicity (AOR = 3.3, 95% CI = 1.9-13.7), ADHD regardless of ODD or CD comorbidity (AOR = 5.8, 95% CI = 1.2-28.7), ODD or CD (AOR = 13.9, 95% CI = 3.3-58.5), Major Depression/Dysthymia (AOR = 2.8, 95% CI = 1.1-6.7) psychiatric disorders, and history of sexual abuse (AOR = 4.6, 95% CI = 1.3-18.4) were associated with the use of prescribed atypical antipsychotics. The aggressive use of atypical antipsychotics, which has unknown metabolic risks, suggests that the efficacy and safety of such treatment strategies for psychiatrically ill children in foster care should be monitored.

Aim: The aim of this study was to analyze the ethyl acetate extract of Nerium indicum (NIE) flower for its antioxidant effect in anxious Sprague-Dawley rats. Materials and Methods: Animals were divided into six groups (n = 6) and treated with 200 mg/kg and 400 mg/kg p.o. of NIE for 21 days to assess its preventive and curative effects. Anxiety was induced by isolating animals socially for 21 days. Elevated plus maze (EPM) and light and dark model were used for measuring anxiety in animals. Oxidative stress parameters such as lipid peroxidation (LPO), superoxide dismutase (SOD), catalase (CAT), and reduced glutathione (GSH) in blood and brain tissue homogenate were monitored after 21 days of social isolation in animals. Results: Rats were treated with NIE 200 mg/kg and 400 mg/kg p.o. Both the treatments showed a significant (P < 0.001) increase in the number of open arm entries and time spent in open arm in EPM when compared with the negative control. Results also demonstrated that there was a significant (P < 0.001) increase in the number of lightbox entries and time spent in light box in light and dark model when compared with negative control. There was a significant (P < 0.001) improvement in endogenous anti-oxidants such as SOD, CAT, reduced GSH, and decreased levels of LPO in blood and brain tissue when compared with the negative control. Conclusion: The present study suggests the role of NIE in the treatment of anxiety, possibly by modulating the oxidative stress.

The mother-infant relationship is an instinctive phenomenon, and loss of maternal care in early life influences neonatal development, behavior and physiologic responses.(1,2) Furthermore, the early loss may affect the vulnerability of the infant to neuropsychiatric disorders, such as childhood anxiety disorders, personality disorders and depression, over its lifespan.(3,4) Fluoxetine is prescribed worldwide for depression and is often used in the treatment of childhood mental problems related to maternal separation or loss of maternal care.(5,6) In the present study, fluoxetine was administrated to rats with maternal separation to determine its effects on neuronal development, in particular with respect to cell proliferation and apoptosis in the dentate gyrus of the hippocampus. Rat pups were separated from their mothers and socially isolated on postnatal day 14 and were treated with fluoxetine (5 mg kg(-1)) and 5-bromo-2'-deoxyuridine (BrdU) (50 mg kg(-1)) for 7 days, after which immunohistochemistry and a terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) staining were carried out. In the pups with maternal separation treated with fluoxetine, the number of BrdU-positive cells was significantly increased and that of TUNEL-positive cells was significantly decreased in the dentate gyrus compared to pups with maternal separation that did not receive fluoxetine treatment. These findings indicate that fluoxetine affects new cell proliferation and apoptosis, and we propose that fluoxetine may be useful in the treatment of maternal separation-related diseases.

Drugs that selectively inhibit serotonin reuptake are effective treatments for adults with mood and anxiety disorders, but limited data are available on the safety and efficacy of serotonin-reuptake inhibitors in children with anxiety disorders. We studied 128 children who were 6 to 17 years of age; who met the criteria for social phobia, separation anxiety disorder, or generalized anxiety disorder; and who had received psychological treatment for three weeks without improvement. The children were randomly assigned to receive fluvoxamine (at a maximum of 300 mg per day) or placebo for eight weeks and were evaluated with rating scales designed to assess the degree of anxiety and impairment. Children in the fluvoxamine group had a mean (+/-SD) decrease of 9.7+/-6.9 points in symptoms of anxiety on the Pediatric Anxiety Rating Scale (range of possible scores, 0 to 25, with higher scores indicating greater anxiety), as compared with a decrease of 3.1+/-4.8 points among children in the placebo group (P<0.001). On the Clinical Global Impressions-Improvement scale, 48 of 63 children in the fluvoxamine group (76 percent) responded to the treatment, as indicated by a score of less than 4, as compared with 19 of 65 children in the placebo group (29 percent, P<0.001). Five children in the fluvoxamine group (8 percent) discontinued treatment because of adverse events, as compared with one child in the placebo group (2 percent). Fluvoxamine is an effective treatment for children and adolescents with social phobia, separation anxiety disorder, or generalized anxiety disorder.

Sixty-seven dogs that showed signs of distress when separated from their owners (destructiveness, excessive vocalisation and house soiling) and hyperattachment were used in a randomised, blind trial to assess the potential value of a dog-appeasing pheromone in reducing the unacceptable behaviours. For ethical reasons, there was no placebo group and the effects of the pheromone were compared with the effects of clomipramine which is regularly used to treat this type of problem. The undesirable behaviours decreased in both groups, but the overall assessment by the owners indicated that there was no significant difference between the two treatments, although there were fewer undesirable events in the dogs treated with the pheromone, and the administration of the pheromone appeared to be more convenient.

Clinical research has indicated that antidepressants are efficacious in the treatment of anxiety disorders, especially when repeatedly administered. However, few animal models of anxiety are sensitive to antidepressants, a finding that may be due to procedures limited to acute administrations. The purpose of the present research was to further validate the chick separation-stress paradigm as an animal model of anxiety by examining its sensitivity to the monoamine oxidase inhibitor (MAOI) phenelzine (6.25, 12.5, 25.0 mg/kg), the tricyclic antidepressant (TCA) imipramine (5.0, 10.0, 20.0 mg/kg), the selective serotonin reuptake inhibitor (SSRI) citalopram (1.0, 2.5, 5.0 mg/kg), and the norepinephrine reuptake inhibitor (NRI) maprotiline (5.0, 10.0, 20.0 mg/kg) under acute (no pretreatment) or repeated (3 or 6 days pretreatment) administration procedures. Following any pretreatment, 8-day-old chicks received their respective vehicle or drug probe injection 15 min before tests in either a \"mirror\" (low stress) or \"no mirror\" (high stress) condition for a 180-s isolation period. The dependent measures were distress vocalizations to index separation stress and sleep onset latency to index sedation. The model was sensitive to acutely administered phenelzine (MAOI), imipramine (TCA), and maprotiline (NRI), but not citalopram (SSRI) and retained its sensitivity to these drug probes across both repeated administration procedures. None of the drug probes possessed any sedative properties. These results help extend the validity and utility of the chick separation-stress paradigm as an animal model of anxiety by demonstrating its sensitivity to antidepressants under both acute and repeated administration procedures.