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Effect of valproate and pregabalin on human anxiety-like behaviour in a randomised controlled trial.

ABSTRACT: Valproate is an anticonvulsant drug with strong preclinical evidence for reducing anxiety behaviour in rodents but no clear clinical evidence. To motivate clinical trials, we here investigate the use of valproate in a translational human model of anxiety behaviour. In a double-blind, randomised, placebo-controlled trial, n?=?118 healthy participants played a previously validated approach/avoidance conflict computer game to measure anxiety-like behaviour, while under 400?mg valproate, under 200?mg of the established anxiolytic/anticonvulsant pregabalin, or under placebo. Saccadic peak velocity and subjective ratings were assessed to control for drug-induced sedation. Compared to placebo, valproate and pregabaline were anxiolytic in the primary outcome, and several secondary outcomes. Bayesian model comparison decisively demonstrated no differences between the two drugs. Subjective and objective sedation was significantly more pronounced under pregabalin than valproate, but did not explain anxiolytic effects. We demonstrate acute anxiolytic properties of valproate in healthy humans. Both drugs have similar anxiolytic properties at the doses used. Valproate is less sedative than pregabalin. Our results suggest clinical trials on the use of valproate in anxiolytic treatment. More generally, we propose a strategy of screening drugs in human preclinical models that can directly be compared across species, such as the approach/avoidance conflict computer game used here. This approach could thus facilitate translational anxiety research.

SUBMITTER: Bach DR

PROVIDER: S-EPMC6095858 | biostudies-other | 2018 Aug

REPOSITORIES: biostudies-other

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Effect of valproate and pregabalin on human anxiety-like behaviour in a randomised controlled trial.

Bach Dominik R DR Korn Christoph W CW Vunder Johanna J Bantel Antonia A

Translational psychiatry 20180816 1

Valproate is an anticonvulsant drug with strong preclinical evidence for reducing anxiety behaviour in rodents but no clear clinical evidence. To motivate clinical trials, we here investigate the use of valproate in a translational human model of anxiety behaviour. In a double-blind, randomised, placebo-controlled trial, n = 118 healthy participants played a previously validated approach/avoidance conflict computer game to measure anxiety-like behaviour, while under 400 mg valproate, under 200 m ...[more]

PMID: 30115911

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Project description:OBJECTIVE:To determine the effectiveness of a novel interdisciplinary treatment compared with usual care on weight loss in overweight and obese adult volunteers. DESIGN:Single blinded controlled trial. Participants randomly assigned to usual care (C, general guideline-based diet and exercise advice), intervention (I, interdisciplinary protocol) or intervention + a healthy food supplement (30 g walnuts/day) (IW). SETTING:Community based study, Illawarra region, south of Sydney, Australia. PARTICIPANTS:Generally well volunteer adult residents, 25-54 years, body mass index (BMI) 25-40kg/m2 were eligible. At baseline 439 were assessed, 377 were randomised, 298 completed the 3-month intensive phase and 178 completed the 12-month follow-up. INTERVENTIONS:Treatment was provided at clinic visits intensively (0 months, 1 month, 2 months, 3 months) then quarterly to 12 months. Support phone calls were quarterly. All participants underwent blinded assessments for diet, exercise and psychological status. PRIMARY AND SECONDARY MEASURES:The primary outcome was difference in weight loss between baseline and 12 months (clinically relevant target 5% loss). Secondary outcomes were changes in blood pressure, fasting blood glucose and lipids, and changes in diet, exercise and psychological parameters. RESULTS:At 12 months, differences in weight loss were identified (p<0.001). The I group lost more than controls at 3 months (91.11 (92.23,90.00), p<0.05) and the IW more than controls at 3 months (91.25 (92.35,90.15), p<0.05) and 6 months (92.20 (93.90,90.49), p<0.01). The proportion achieving 5% weight loss was significantly different at 3 months, 6 months and 9 months (p=0.04, p=0.03, p=0.03), due to fewer controls on target at 3 months, 6 months and 9 months and more IW participants at 6 months. Reductions in secondary outcomes (systolic blood pressure, blood glucose/lipid parameters and lifestyle measures) followed the pattern of weight loss. CONCLUSIONS:An interdisciplinary intervention produced greater and more clinically significant and sustained weight loss compared with usual care. The intensive phase was sufficient to reach clinically relevant targets, but long-term management plans may be required. TRIAL REGISTRATION NUMBER:ANZCTRN 12614000581662; Post-results.

Project description:IntroductionWith the development of new neuroimaging tools it has become possible to assess neurochemical alterations in patients experiencing chronic pain and to determine how these factors change during pharmacological treatment. The goal of this study was to examine the exact neurochemical mechanism underlying pregabalin treatment, utilizing magnetic resonance spectroscopy (1H-MRS), in a population of patients with painful diabetic polyneuropathy (PDN), with the overall aim to ultimately objectify the clinical effect of pregabalin.MethodsA double blind, randomized, placebo-controlled study was conducted. A total of 27 patients with PDN were enrolled in the study, of whom 13 received placebo treatment (control group) and 14 received pregabalin (intervention group). Pregabalin treatment consisted of stepwise dose escalation over the study period from 75 mg daily ultimately to 600 mg daily. 1H-MRS was performed at 3T on four regions of interest in the brain: the rostral anterior cingulate cortex (rACC), left and right thalamus and prefrontal cortex. The absolute concentrations of N-acetyl aspartate, glutamate, glutamine, gamma-amino-butyric-acid (GABA), glucose (Glc) and myo-inositol (mINS) were determined using LCModel.ResultsThe concentration of most neurometabolites in the placebo and pregabalin group did not significantly differ over time, with only a small significant difference in Glc level in the left thalamus (p = 0.049). Comparison of the effects of the different doses revealed significant differences for mINS in the rACC (baseline 2.42 ± 1.21 vs. 450 mg 1.58 ± 0.94; p = 0.022) and dorsolateral prefrontal cortex (75 mg 2.38 ± 0.89 vs. 450 mg 1.59 ± 0.85; p = 0.042) and also for GABA in the rACC (75 mg 0.53 ± 0.51 vs. 225 mg 0.28 ± 0.19; p = 0.014).ConclusionNo differences were found in metabolite concentrations between the placebo (control) and intervention groups, but some differences, although small, were found between the different doses.Trial registrationThis study is registered at ClinicalTrials.gov (NCT01180608).FundingLyrica Independent Investigator Research Award (LIIRA) 2010 (Pfizer) funded the study.

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Project description:BackgroundMany persons with autism spectrum disorder (ASD) are treated in long-term specialised care. In this population, suicidal behaviour troubles patients, families, and specialists in the field because it is difficult to treat. At present, there is no documented effective therapy for suicidal behaviour in ASD (Autism Research 7:507-521, 2014; Crisis 35:301-309, 2014). Dialectical Behaviour Therapy (DBT) is an efficacious treatment programme for chronically suicidal and/or self-harm behaviour in patients with Borderline Personality Disorder (J Psychiatry 166:1365-1374, 2014; Linehan MM. Cognitive behavioural therapy of borderline personality disorder. 1993). This study will evaluate the efficacy of DBT in persons with ASD and suicidal/ self- destructive behaviour in a multicentre randomised controlled clinical trial.MethodOne hundred twenty-eight persons with autism and suicidal and/or self-harming behaviour will be recruited from specialised mental healthcare services and randomised into two conditions: 1) the DBT condition in which the participants have weekly individual cognitive behavioural therapy sessions and a 2.5 h skills training group session twice per week during 6 months, and 2) the treatment as usual condition which consists of weekly individual therapy sessions of 30-45 min with a psychotherapist or social worker. Assessments will take place at baseline, at post-treatment (6 months), and after a follow-up period of 12 months. The mediators will also be assessed at 3 months. The primary outcome is the level of suicidal ideation and behaviour. The secondary outcomes are anxiety and social performance, depression, core symptoms of ASD, quality of life, and cost-utility. Emotion regulation and therapeutic alliance are hypothesised to mediate the effects on the primary outcome.DiscussionThe results from this study will provide an evaluation of the efficacy of DBT treatment in persons with ASD on suicidal and self-harming behaviour. The study is conducted in routine mental health services which enhances the generalisability of the study results to clinical practice.Trial registrationISRCTN96632579. Registered 1 May 2019. Retrospectively registered.

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Effect of valproate and pregabalin on human anxiety-like behaviour in a randomised controlled trial.

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Effect of valproate and pregabalin on human anxiety-like behaviour in a randomised controlled trial.

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