Anxiolytic Efficacy Research Articles

Neuroprotective effects of a novel translocator protein (18 kDa) ligand, ZBD-2, against focal cerebral ischemia and NMDA-induced neurotoxicity.

Ligands of the translocator protein (18 kDa) (TSPO) have demonstrated rapid anxiolytic efficacy in stress responses and stress-related disorders. This protein is involved in the synthesis of endogenous neurosteroids including pregnenolone, dehydroepiandrosterone, and progesterone. These neurosteroids promote γ-aminobutyric acid-mediated neurotransmission in the central neural system (CNS). A TSPO ligand, N-benzyl-N-ethyl-2-(7,8-dihydro-7-benzyl-8-oxo-2-phenyl-9H-purin-9-yl) acetamide (ZBD-2) was recently synthesized. The purpose of the present study was to investigate the neuroprotective effects of ZBD-2 and. In cultured cortical neurons, treatment with ZBD-2 attenuated excitotoxicity induced by N-methyl-d-aspartate (NMDA) exposure. It significantly decreased the number of apoptotic cells by downregulating GluN2B-containing NMDA receptors (NMDARs), the ratio of Bax/Bcl-2, and levels of pro-caspase-3. Systemic treatment of ZBD-2 provided significant neuroprotection in mice subjected to middle cerebral artery occlusion. These findings provide direct evidence that neuroprotection by ZBD-2 is partially mediated by inhibiting GluN2B-containing NMDA receptor-mediated excitotoxicity.

Video Distraction and Parental Presence for the Management of Preoperative Anxiety and Postoperative Behavioral Disturbance in Children: A Randomized Controlled Trial.

The anxiolytic efficacy of video watching, in the absence of parents, during the mask induction of anesthesia in young children with high separation anxiety has not been clearly established. We performed this study to determine whether the effect of video distraction on alleviating preoperative anxiety is independent of parental presence and whether a combination of both interventions is more effective than either single intervention in alleviating preoperative anxiety and postoperative behavioral disturbance in preschool children. In this prospective trial, 117 children aged 2 to 7 years scheduled for elective minor surgery were randomly allocated to 1 of 3 groups, a video distraction group (group V), a parental presence group (group P), or a combination of video distraction plus parental presence group (group VP) during induction of sevoflurane anesthesia. The Modified Yale Preoperative Anxiety Scale (mYPAS) was used to assess anxiety in the preoperative holding area (baseline), immediately after entry to the operating room, and during mask induction. Compliance during induction, emergence delirium during recovery, and negative behavioral changes at 1 day and 2 weeks postoperatively were also assessed. The mYPAS scores were comparable (P = 0.558), and the number of children exhibiting baseline anxiety (an mYPAS score > 30) were not different among the 3 groups in the preoperative holding area (P = 0.824). After intervention, the changes in mYPAS scores from baseline to induction were not different among the 3 groups (P = 0.049). The proportion of children with increased mYPAS scores was higher in group P compared with group V from baseline to operating room entry (Bonferroni-adjusted 95% confidence interval for difference, 2 to 49) but similar from baseline to induction in all 3 groups. Although children in group V were more cooperative during mask induction than those in the other 2 groups (P < 0.001 versus group P and P = 0.001 versus group VP), no significant intergroup differences were observed in the incidence of emergence delirium or new-onset negative behavioral change after surgery. Video distraction, parental presence, or their combination showed similar effects on preoperative anxiety during inhaled induction of anesthesia and postoperative behavioral outcomes in preschool children having surgery.

Efficacy of orally administered Silexan in patients with anxiety-related restlessness and disturbed sleep – A randomized, placebo-controlled trial

The anxiolytic effect of Silexan, a patented active substance with an essential oil produced from Lavandula angustifolia flowers, was investigated in patients with anxiety-related restlessness and disturbed sleep. 170 out-patients with a diagnosis of restlessness (ICD-10 R45.1), a Hamilton Anxiety Scale (HAMA) total score ≥18 points and ≥2 points for HAMA items ‘Tension’ and ‘Insomnia’ participated in this randomized, double-blind trial and received 80mg Silexan or placebo once daily for 10 weeks. Patients with clinically important other psychiatric or neurological disorders potentially interfering with the assessment of treatment efficacy were excluded. Outcome variables were the HAMA as well as the Pittsburgh Sleep Quality Index (PSQI), the Zung Self-rating Anxiety Scale, a State Check inventory and the Clinical Global Impressions questionnaire. In the Silexan group the HAMA total score decreased from an average of 25.5±6.0 points at baseline to 13.7±7.0 points at treatment end, compared to a decrease from 26.5±6.1 to 16.9±9.8 for placebo, corresponding to decreases of 12.0 and 9.3 points (marginal means), respectively (group difference: p=0.03, ANCOVA with factor treatment and baseline value as covariate). In all outcome measures the treatment effect of Silexan was more pronounced than with placebo. According to the HAMA, 48.8% and 33.3% of the patients were responders (Silexan, placebo; reduction ≥50%; p=0.04) and 31.4% and 22.6% achieved remission (HAMA<10; p=0.20). 33.7% (Silexan) and 35.7% (placebo) of the participants reported adverse events. The study confirms the calming and anxiolytic efficacy of Silexan.

Clinical trial of pregabalin as an add-on therapy in children with refractory epilepsy

Epilepsy is the most common neurological disorder worldwide. One-third of epileptic patients do not respond after treatment with first- or second-line antiepileptic drugs. Pregabalin is a novel antiseizure drug with established anxiolytic and analgesic efficacy. In this study, we evaluated the efficacy and tolerability of pregabalin as an adjunctive therapy in a group of children with intractable epilepsy. From October 2011 to September 2012, 67 children with refractory epilepsy who visited the pediatric neurology clinic of Mofid Children’s Hospital were enrolled in this study. The patients were treated with pregabalin. Reduction in seizure frequency and severity were compared after 1 and 6 mo of treatment initiation. During follow-up, >50% reduction in seizure frequency or severity was observed as a response to the drug. Of the 60 children who reached the last stage, 29 (48.3%) were boys and 31 (51.7%) were girls. The age of the children ranged between 6 mo and 16 yr, with a mean age of 71 ± 42.9 mo. Pregabalin reduced seizure frequency up to 2.41 ± 2.38 (48% decline) and 2.75 ± 2.38 (40.86% decline) after 1 and 6 mo of treatment initiation, respectively. There was a significant difference between seizure frequency at 1 (P

Anxiolytic efficacy of repeated oral capsaicin in rats with partial aberration of oral sensory relay to brain

ObjectiveThis study was conducted to examine if taste over load with oral capsaicin improves the adverse behavioural effects induced by partial aberration of oral sensory relays to brain with bilateral transections of the lingual and chorda tympani nerves. DesignMale Sprague-Dawley rats received daily 1ml of 0.02% capsaicin or water drop by drop into the oral cavity following the bilateral transections of the lingual and chorda tympani nerves. Rats were subjected to ambulatory activity, elevated plus maze and forced swim tests after 11th, 14th and 17th daily administration of capsaicin or water, respectively. The basal and stress-induced plasma corticosterone levels were examined after the end of behavioural tests. ResultsAmbulatory counts, distance travelled, centre zone activities and rearing were increased, and rostral grooming decreased, during the activity test in capsaicin treated rats. Behavioural scores of capsaicin rats during elevated plus maze test did not differ from control rats. Immobility during the swim test was decreased in capsaicin rats with near significance (P=0.0547). Repeated oral capsaicin increased both the basal level and stress-induced elevation of plasma corticosterone in rats with bilateral transections of the lingual and chorda tympani nerves. DiscussionIt is concluded that repeated oral administration of capsaicin reduces anxiety-like behaviours in rats that received bilateral transections of the lingual and chorda tympani nerves, and that the increased corticosterone response, possibly modulating the hippocampal neural plasticity, may be implicated in the anxiolytic efficacy of oral capsaicin.

Anxiolytic-like effects of translocator protein (TSPO) ligand ZBD-2 in an animal model of chronic pain.

The activation of Translocator protein (18 kDa) (TSPO) has been demonstrated to mediate rapid anxiolytic efficacy in stress response and stress-related disorders. This protein is involved in the synthesis of endogenous neurosteroids that promote γ-aminobutyric acid (GABA)-mediated neurotransmission in the central neural system. However, little is known about the functions and the underlying mechanisms of TSPO in chronic pain-induced anxiety-like behaviors. The novel TSPO ligand N-benzyl-N-ethyl-2-(7,8-dihydro-7-benzyl-8-oxo-2-phenyl-9H-purin-9-yl) acetamide (ZBD-2) was used in the present study. We found that ZBD-2 (0.15 or 1.5 mg/kg) significantly attenuated anxiety-like behaviors in mice with chronic inflammatory pain induced by hindpaw injection of complete Freund’s adjuvant (CFA). However, the treatment did not alter the nociceptive threshold or inflammation in the hindpaw. Hindpaw injection of CFA induced the upregulation of TSPO, GluR1-containing α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, and NR2B-containing N-methyl-d-aspartate (NMDA) receptors in the basolateral amygdala (BLA). ZBD-2 administration reversed the alterations of the abovementioned proteins in the BLA of the CFA-injected mice. Electrophysiological recording revealed that ZBD-2 could prevent an imbalance between excitatory and inhibitory transmissions in the BLA synapses of CFA-injected mice. Therefore, as the novel ligand of TSPO, ZBD-2 induced anxiolytic effects, but did not affect the nociceptive threshold of mice under chronic pain. The anxiolytic effects of ZBD-2 were related to the regulation of the balance between excitatory and inhibitory transmissions in the BLA.

Prototypical anxiolytics do not reduce anxiety-like behavior in the open field in C57BL/6J mice

Understanding and effectively treating anxiety disorders are a challenge for both scientists and clinicians. Despite a variety of available therapies, the efficacy of current treatments is still not optimal and adverse side effects can result in non-compliance. Animal models have been useful for studying the underlying biology of anxiety and assessing the anxiolytic properties of potential therapeutics. The open field (OF) is a commonly used assay of anxiety-like behavior. The OF was developed and validated in rats and then transferred to use in the mouse with only limited validation. The present study tests the efficacy of prototypical benzodiazepine anxiolytics, chlordiazepoxide (CDP) and diazepam (DZ), for increasing center time in the OF in C57BL/6J (B6) mice. Multiple doses of CDP and DZ did not change time spent in the center of the OF. Increasing illumination in the OF did not alter these results. The non-benzodiazepine anxiolytic, buspirone (BUSP) also failed to increase center time in the OF while the anxiogenic meta-chlorophenylpiperazine (mCPP) increased center time. Additional inbred mouse strains, BALB/cJ (BALB) and DBA/2J (D2) did not show any change in center time in response to CDP. Moreover, evaluation of CDP in B6 mice in the elevated plus maze (EPM), elevated zero maze (EZM) and light dark assay (LD) did not reveal changes in anxiety-like behavior while stress-induced hyperthermia (SIH) was decreased by DZ. Pharmacokinetic (PK) studies suggest that adequate CDP is present to induce anxiolysis. We conclude that the measure of center time in the OF does not show predictive validity for anxiolysis in these inbred mouse strains.

A randomised clinical trial comparing the analgesic and anxiolytic efficacy and tolerability of Stilpane® and Tramacet® after third molar extraction

Background: Successful treatment of moderate to severe acute pain often necessitates several analgesics that target different sites of the nociceptive pathway. Fixed-dose combination analgesics fac...

Enhancing neurosteroid synthesis--relationship to the pharmacology of translocator protein (18 kDa) (TSPO) ligands and benzodiazepines.

The treatment of anxiety disorders is still a challenge; novel pharmacological approaches that combine rapid anxiolytic efficacy with fewer side effects are needed. A promising target for such compounds is the mitochondrial translocator protein (18 kDa) (TSPO). TSPO plays an important role for the synthesis of neurosteroids, known to modulate GABAA receptors, thereby exerting anxiolytic effects. We investigated the pharmacological profile of 2 well established TSPO ligands (XBD173 and etifoxine) compared to the benzodiazepine diazepam with regard to TSPO binding affinity, TSPO expression and neurosteroidogenesis. In BV-2 microglia and C6 glioma cells all compounds significantly enhanced TSPO protein expression. Radioligand binding assays revealed the highest binding affinity to TSPO for XBD173, followed by diazepam and etifoxine. Pregnenolone synthesis was most potently enhanced by etifoxine. Etifoxine turned out to be the most potent enhancer of neurosteroidogenesis, although its binding affinity to TSPO was lowest. These results indicate that the efficacy of TSPO ligands to stimulate neurosteroid synthesis, thereby leading to anxiolytic effects cannot be concluded from their binding affinity to TSPO.

Miejsce kwetiapiny o przedłużonym uwalnianiu w terapii osób z zaburzeniami psychicznymi

This article presents a summary of available data on the use of quetiapine extended release (QUE-XR). QUE-XR is an example of an atypical antipsychotic drug that can be used inasingle dose, thereby simplifying the treatment regimen. From the therapeutic standpoint, this issue is of paramount importance, since approximately 50% of patients have adherence issues. Therefore, availability of the drug which is comfortable in administration can significantly improve treatment outcomes. Due to its antipsychotic, antidepressive, mood stabilizing and anxiolytic efficacy, QUE-XR seems to be a promising drug with potentially broad spectrum of indications (in patients with schizophrenia, bipolar disorder, major depression and some anxiety disorders - both in the acute phase of treatment, and the maintenance treatment). Notably, QUE-XR seems to ameliorate sleep disturbances, and it may also improve patients' quality of life (as suggested by some studies). Due to the simple dosing regimen of QUE-XR, conducting therapy with this drug may contribute to the improvement of compliance. Yet, the primary clinical criterion for selection of the type of formulation of quetiapine should be the individual preferences of the patient, and the knowledge and experience of thetreating physician.

No interacting influence of lavender oil preparation silexan on oral contraception using an ethinyl estradiol/levonorgestrel combination.

PurposeSilexan is an oral Lavender oil preparation with proven anxiolytic efficacy. Given the high prevalence of anxiety and restlessness in younger women, oral contraceptives and Silexan will likely be co-administered.MethodsA double-blind, randomised, 2-period crossover study was performed to investigate the effects of Silexan on the pharmacokinetics and pharmacodynamics of Microgynon®, a combination oral contraceptive containing ethinyl estradiol 0.03 mg (EE) and levonorgestrel 0.15 mg (LNG) in healthy, fertile, adult females. During 2 consecutive cycles of 28 days, oral contraception was given for 21 days combined with 1 × 160 mg/day Silexan or placebo. Plasma concentration–time profiles of EE and LNG were obtained on day 18 ± 1 up to 24 h after dosing. The primary outcome measure was the area under the concentration–time curve over a dosing interval of τ = 24 h (AUCτ) for EE and LNG plasma levels. An interaction with Silexan was formally excluded if the 90 % confidence interval for the AUCτ ratio during co-administration with Silexan or placebo was included within the range of 0.80–1.25. Secondary outcomes included EE and LNG peak concentration (C max) and time to C max (t max), follicle size, endometrial thickness, the Hoogland score, and serum levels of estradiol, progesterone, and sex hormone-binding globulin.ResultsA total of 24 women (mean age 27.3 years; mean body mass index 22.2 kg/m2) participated. The confidence intervals for the EE and LNG AUCτ and C max ratios fell within the pre-specified limits, indicating no interaction (point estimates [Silexan/placebo] AUCτ EE 0.97, LNG 0.94; C max EE 0.99, LNG 0.96). For LNG, t max was slightly delayed. No secondary outcome indicated any impairment of contraceptive efficacy.ConclusionsCo-administration of Silexan did not affect the efficacy of a combination oral contraceptive containing EE and LNG and was well tolerated.

Pregabalin: a review of its use in adults with generalized anxiety disorder.

Pregabalin (Lyrica(®)), a well established anxiolytic agent, has been approved in the EU for the treatment of generalized anxiety disorder (GAD) in adults. It has a distinct mechanism of action relative to other anti-anxiety agents (α2δ binding at presynaptic voltage dependent calcium channels leading to inhibition of excitatory neurotransmission), a rapid onset of effect (typically ≤1week) and broad spectrum activity against both the psychic and somatic symptoms of GAD. In long-term studies, pregabalin maintained improvements in anxiety symptoms that occurred in response to short-term treatment and delayed the time to relapse of GAD compared with placebo. Common comorbidities of GAD, such as insomnia, gastrointestinal symptoms and subsyndromal depression, have no effect on the anxiolytic efficacy of, and moreover are specifically improved by, pregabalin. Treatment with pregabalin is generally well tolerated; the drug has an adverse event profile that includes dizziness, somnolence and weight gain. The potential for abuse of pregabalin is low; the risk of withdrawal symptoms is generally low when the drug is discontinued gradually (over 1week). Alongside selective serotonin reuptake inhibitors (SSRIs) and serotonin-noradrenaline reuptake inhibitors (SNRIs), pregabalin is considered a first-line agent for the long-term treatment of GAD by the World Federation of Societies of Biological Psychiatry. It should be stressed, however, that definitive head-to-head studies comparing pregabalin with SSRI/SNRIs, including in patients with GAD and co-morbid major depressive disorder, are currently lacking. Recently, a study of SSRI/SNRI augmentation with pregabalin yielded positive results, while another study of switching from long-term benzodiazepine therapy to pregabalin was inconclusive; further investigations on these topics are warranted.

Effects of the anti-multiple sclerosis immunomodulator laquinimod on anxiety and depression in rodent behavioral models.

Laquinimod is a novel oral immunomodulatory drug for the treatment of multiple sclerosis (MS). Considering the frequent co-morbidity of MS with anxiety and depression, we sought to assess the antidepressant and anxiolytic effects of laquinimod in mouse models. Laquinimod (0.5-25 mg/kg), fluoxetine (10 mg/kg) or vehicle were administered for 4-14 days to adult Balb/c mice, followed by behavioral tests and brain BDNF analysis. Following a 4-day administration of laquinimod (5 and 25 mg/kg), an increase in motivated behavior was observed in the forced swim test (p < 0.01 vs. controls). In the open field test, laquinimod (0.5-5 mg/kg), but not fluoxetine, significantly increased motility (p < 0.05), whereas both decreased anxiety behavior (p < 0.01), evident only for laquinimod (5 mg/kg) in the elevated plus maze (p < 0.05). Following 7 days of administration, both drugs decreased anxiety behavior in the elevated plus maze and marble burying tests (p < 0.001 and p < 0.02, respectively). After 14 days, only laquinimod (5 mg/kg) demonstrated anxiolytic efficacy in the open field test (p < 0.05), with evidence of increased BDNF in response to 5-25 mg/kg in the hippocampus, but not frontal cortex (p < 0.05). In conclusion, laquinimod may possess anxiolytic and antidepressant effects, possibly associated with hippocampal BDNF increase, offering promise for MS patients suffering from psychiatric co-morbidity.

Dopamine and serotonin signaling during two sensitive developmental periods differentially impact adult aggressive and affective behaviors in mice

Pharmacologic blockade of monoamine oxidase A (MAOA) or serotonin transporter (5-HTT) has antidepressant and anxiolytic efficacy in adulthood. Yet, genetically conferred MAOA or 5-HTT hypoactivity is associated with altered aggression and increased anxiety/depression. Here we test the hypothesis that increased monoamine signaling during development causes these paradoxical aggressive and affective phenotypes. We find that pharmacologic MAOA blockade during early postnatal development (P2-P21) but not during peri-adolescence (P22-41) increases anxiety- and depression-like behavior in adult (>P90) mice, mimicking the effect of P2-21 5-HTT inhibition. Moreover, MAOA blockade during peri-adolescence, but not P2-21 or P182-201, increases adult aggressive behavior, and 5-HTT blockade from P22-P41 reduced adult aggression. Blockade of the dopamine transporter, but not the norepinephrine transporter, during P22-41 also increases adult aggressive behavior. Thus, P2-21 is a sensitive period during which 5-HT modulates adult anxiety/depression-like behavior, and P22-41 is a sensitive period during which DA and 5-HT bi-directionally modulate adult aggression. Permanently altered DAergic function as a consequence of increased P22-P41 monoamine signaling might underlie altered aggression. In support of this hypothesis, we find altered aggression correlating positively with locomotor response to amphetamine challenge in adulthood. Proving that altered DA function and aggression are causally linked, we demonstrate that optogenetic activation of VTA DAergic neurons increases aggression. It therefore appears that genetic and pharmacologic factors impacting dopamine and serotonin signaling during sensitive developmental periods can modulate adult monoaminergic function and thereby alter risk for aggressive and emotional dysfunction.

Lavender oil preparation Silexan is effective in generalized anxiety disorder – a randomized, double-blind comparison to placebo and paroxetine

The anxiolytic efficacy of the orally administered lavender oil preparation Silexan was investigated in generalized anxiety disorder (GAD) in comparison to placebo and paroxetine. In this randomized, double-blind, double-dummy trial 539 adults with GAD according to DSM-5 criteria and a Hamilton Anxiety Scale (HAMA) total score ⩾ 18 points participated and received 160 or 80 mg Silexan, 20 mg paroxetine, or placebo once daily for 10 wk. The primary efficacy endpoint was the HAMA total score reduction between baseline and treatment end. The HAMA total score decreased by 14.1 ± 9.3 points for Silexan 160 mg/d, 12.8 ± 8.7 points for Silexan 80 mg/d, 11.3 ± 8.0 points for paroxetine, and 9.5 ± 9.0 points for placebo (mean ± s.d.). Silexan 160 and 80 mg/d were superior to placebo in reducing the HAMA total score (p < 0.01) whereas paroxetine showed a trend towards significance (p = 0.10) in the full analysis set. The difference between paroxetine and placebo was more pronounced in the analysis of observed cases (HAMA total score reduction: p < 0.01). In the Silexan 160 mg/d group 73/121 patients (60.3%) showed a HAMA total score reduction ⩾ 50% of the baseline value and 56 (46.3%) had a total score <10 points at treatment end, compared to 70/135 (51.9%) and 45 (33.3%) for Silexan 80 mg/d, 57/132 (43.2%) and 45 (34.1%) for paroxetine, and 51/135 (37.8%) and 40 (29.6%) for placebo. In addition, Silexan showed a pronounced antidepressant effect and improved general mental health and health-related quality of life. Incidence densities of adverse events (AEs) were 0.006 AEs/d for Silexan 160 mg/d, 0.008 AEs/d for 80 mg/d, 0.011 AEs/d for paroxetine, and 0.008 AEs/d for placebo. In GAD Silexan is more efficacious than placebo. AE rates for Silexan were comparable to placebo and lower than for the active control paroxetine.

Optimization of Bupivacaine Induced Subarachnoid Block by Clonidine: Effect of Different Doses of Oral Clonidine

Background: Various drugs are used for premedication to reduce anxiety and to provide hemodynamic stability. The study was designed to investigate the optimum dose of oral clonidine administered preoperatively with regard to its anxiolytic efficacy and its effect on hemodynamics and sedation. We studied the effect of three different doses of oral clonidine on surgeries below umbilicus which were administered intrathecal bupivacaine. Methods: A placebo controlled double blind study was conducted on 120 patients scheduled for surgeries below umbilicus. Group 1 received oral placebo, group 2 received oral clonidine 3 μg kg-1, group 3 received oral clonidine 4 μg kg-1 and group 4 received oral clonidine 5 μg kg-1 along with 0.5% heavy bupivacaine 0.3 μg kg-1 intrathecally in each group. Outcomes assessed were anxiolysis through VAS, level of sensory block, time to reach highest sensory segment, regression to L1 segment, sedation score, bradycardia and hypotension. Results: There was improved block duration and sedation with the different doses of clonidine. Time for the sensory block to regress to L1 and rescue analgesia was longest in 4 followed by groups 3 and 2. There was significant dose dependent decrease in VAS anxiety score between group 1 and other clonidine groups in intraoperative and post-operative period. However, the episodes of bradycardia and hypotension were highest in 4 group. Conclusion: Preoperative oral clonidine 4 μg kg-1 appears to be the optimum dose for optimization of spinal anaesthesia with bupivacaine as it prolongs the sensory block maximally with minimal side effects.

Efficacy of acupuncture in reducing preoperative anxiety: a meta-analysis.

Background. Acupuncture has been shown to reduce preoperative anxiety in several previous randomized controlled trials (RCTs). In order to assess the preoperative anxiolytic efficacy of acupuncture therapy, this study conducted a meta-analysis of an array of appropriate studies. Methods. Four electronic databases (MEDLINE, EMBASE, CENTRAL, and CINAHL) were searched up to February 2014. In the meta-analysis data were included from RCT studies in which groups receiving preoperative acupuncture treatment were compared with control groups receiving a placebo for anxiety. Results. Fourteen publications (N = 1,034) were included. Six publications, using the State-Trait Anxiety Inventory-State (STAI-S), reported that acupuncture interventions led to greater reductions in preoperative anxiety relative to sham acupuncture (mean difference = 5.63, P < .00001, 95% CI [4.14, 7.11]). Further eight publications, employing visual analogue scales (VAS), also indicated significant differences in preoperative anxiety amelioration between acupuncture and sham acupuncture (mean difference = 19.23, P < .00001, 95% CI [16.34, 22.12]). Conclusions. Acupuncture therapy aiming at reducing preoperative anxiety has a statistically significant effect relative to placebo or nontreatment conditions. Well-designed and rigorous studies that employ large sample sizes are necessary to corroborate this finding.

Evaluation of the antidepressant, anxiolytic and memory-improving efficacy of aripiprazole and fluoxetine in ethanol-treated rats

Some study results indicate a positive effect of aripiprazole (ARI) on impaired cognitive functions caused by brain damage resulting from chronic EtOH abuse. However, other research shows that to manifest itself, an ARI antidepressant effect requires a combined therapy with another selective serotonin reuptake inhibitor antidepressant, namely, fluoxetine (FLX). The aim of this article was to assess antidepressant and anxiolytic effects of ARI as well as its effect on spatial memory in ethanol-treated (alcoholized) rats. On the basis of alcohol consumption pattern, groups of (1) ethanol-preferring rats, with mean ethanol intake above 50%, and (2) ethanol-nonpreferring rats (EtNPRs), with mean ethanol intake below 50% of total daily fluid intake, were formed. The group of EtNPRs was used for this study, subdivided further into three groups administered ARI, FLX and a combination of both, respectively. Behavioral tests such as Porsolt’s forced swimming test, the Morris water maze test and the two-compartment exploratory test were employed. Behavioral test results demonstrated (1) no antidepressant effect of ARI in EtNPRs in subchronic treatment and (2) no procognitive effect of ARI and FLX in EtNPRs in combined single administration. Combined administration of both drugs led to an anxiogenic effect and spatial memory deterioration in study animals. ARI had no antidepressant effect and failed to improve spatial memory in rats. However, potential antidepressant, anxiolytic and procognitive properties of the drug resulting from its mechanism of action encourage further research aimed at developing a dose of both ARI and FLX that will prove such effects in alcoholized EtNPRs.

Orexin-1 receptor antagonism fails to reduce anxiety-like behaviour in either plus-maze-naïve or plus-maze-experienced mice

Although several lines of evidence have recently implicated orexins and their receptors in fear and anxiety, there is also a growing number of apparently inconsistent and/or negative findings. In the present study, we have used ethological methods to comprehensively profile the behavioural effects of the orexin-1 receptor antagonist SB-334867 (3–30mg/kg) in mice exposed to the elevated plus-maze. Two experiments were performed, the first involving test-naïve animals and the second using prior undrugged experience of the maze to induce a qualitatively different emotional response to that seen on first exposure. In Experiment 1, a reference benzodiazepine (chlordiazepoxide, CDP, 15mg/kg) produced a robust anxioselective profile comprising substantial increases in open arm exploration and reduced risk assessment without any signiifcant change in general activity levels. In contrast, SB-334867 failed to produce any behavioural effects over the dose range tested. In Experiment 2, 5min undrugged experience of the maze 24h prior to testing increased open arm avoidance and abolished the anxiolytic efficacy of CDP. Despite this altered baseline, SB-334867 again failed to alter plus-maze behaviour. These findings agree with several recent reports that orexin receptor antagonists, such as SB-334867 and almorexant, do not alter basal anxiety levels in rats but markedly contrast with the anxiolytic-like effects of the same agents when anxiety levels have been exacerbated by fear conditioning, drug challenge or hypercapnia. This unique pattern of activity suggests that orexin receptor antagonists may have therapeutic value in those clinical anxiety disorders characterised by intense emotional arousal.

The role of the serotonergic and GABA system in translational approaches in drug discovery for anxiety disorders

There is ample evidence that genetic factors play an important role in anxiety disorders. In support, human genome-wide association studies have implicated several novel candidate genes. However, illumination of such genetic factors involved in anxiety disorders has not resulted in novel drugs over the past decades. A complicating factor is the heterogeneous classification of anxiety disorders in the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) and diverging operationalization of anxiety used in preclinical and clinical studies. Currently, there is an increasing focus on the gene × environment (G × E) interaction in anxiety as genes do not operate in isolation and environmental factors have been found to significantly contribute to the development of anxiety disorders in at-risk individuals. Nevertheless, extensive research on G × E mechanisms in anxiety has not resulted in major breakthroughs in drug discovery. Modification of individual genes in rodent models has enabled the specific study of anxiety in preclinical studies. In this context, two extensively studied neurotransmitters involved in anxiety are the gamma-aminobutyric acid (GABA) and 5-HT (5-hydroxytryptamine) system. In this review, we illustrate the complex interplay between genes and environment in anxiety processes by reviewing preclinical and clinical studies on the serotonin transporter (5-HTT), 5-HT1A receptor, 5-HT2 receptor, and GABAA receptor. Even though targets from the serotonin and GABA system have yielded drugs with known anxiolytic efficacy, the relation between the genetic background of these targets and anxiety symptoms and development of anxiety disorders is largely unknown. The aim of this review is to show the vast complexity of genetic and environmental factors in anxiety disorders. In light of the difficulty with which common genetic variants are identified in anxiety disorders, animal models with translational validity may aid in elucidating the neurobiological background of these genes and their possible role in anxiety. We argue that, in addition to human genetic studies, translational models are essential to map anxiety-related genes and to enhance our understanding of anxiety disorders in order to develop potentially novel treatment strategies.