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

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.

Amygdala Lesions Reduce Anxiety-like Behavior in a Human Benzodiazepine-Sensitive Approach-Avoidance Conflict Test.

BACKGROUND: Rodent approach-avoidance conflict tests are common preclinical models of human anxiety disorder. Their translational validity mainly rests on the observation that anxiolytic drugs reduce rodent anxiety-like behavior. Here, we capitalized on a recently developed approach-avoidance conflict computer game to investigate the impact of benzodiazepines and of amygdala lesions on putative human anxiety-like behavior. In successive epochs of this game, participants collect monetary tokens on a spatial grid while under threat of virtual predation. METHODS: In a preregistered, randomized, double-blind, placebo-controlled trial, we tested the effect of a single dose (1 mg) of lorazepam (n = 59). We then compared 2 patients with bilateral amygdala lesions due to Urbach-Wiethe syndrome with age- and gender-matched control participants (n = 17). Based on a previous report, the primary outcome measure was the effect of intra-epoch time (i.e., an adaptation to increasing potential loss) on presence in the safe quadrant of the spatial grid. We hypothesized reduced loss adaptation in this measure under lorazepam and in patients with amygdala lesions. RESULTS: Lorazepam and amygdala lesions reduced loss adaptation in the primary outcome measure. We found similar results in several secondary outcome measures. The relative reduction of anxiety-like behavior in patients with amygdala lesions was qualitatively and quantitatively indistinguishable from an impact of anterior hippocampus lesions found in a previous report. CONCLUSIONS: Our results establish the translational validity of human approach-avoidance conflict tests in terms of anxiolytic drug action. We identified the amygdala, in addition to the hippocampus, as a critical structure in human anxiety-like behavior.