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Randomized Controlled Trial
. 2018 Aug 16;8(1):157.
doi: 10.1038/s41398-018-0206-7.

Effect of Valproate and Pregabalin on Human Anxiety-Like Behaviour in a Randomised Controlled Trial

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Free PMC article
Randomized Controlled Trial

Effect of Valproate and Pregabalin on Human Anxiety-Like Behaviour in a Randomised Controlled Trial

Dominik R Bach et al. Transl Psychiatry. .
Free PMC article

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.

Conflict of interest statement

The authors declare that they have no conflict of interest.

Figures

Fig. 1
Fig. 1. Experimental design.
a Study procedure. b Behavioural approach-avoidance conflict (AAC) computer game. A human player (green triangle) is foraging for tokens (yellow rhombi), which contribute to financial reimbursement at the end of the game. At any time, 10 tokens are present and are replaced in random position when collected. Collected tokens are shown in the upper left corner, above the grid. Meanwhile, a predator (grey circle) is inactive in a corner of the grid, and can attack the human player at any given time according to three probabilities specified by the frame colour. To avoid being caught by the predator, the player can seek shelter in a safe place. Presence in the safe place constitutes the primary outcome measure. The safe place is always diagonal to the initial predator position. During the chase phase, when the predator wakes up, the frame colour turns red. All tokens from this epoch are lost when the player is caught
Fig. 2
Fig. 2. Effect of valproate and pregabalin on primary and secondary outcomes.
Line graphs show evolution of outcome measures over 15 s epochs, evaluated in 1 s time bins. Inset bar graphs reflect the a priori contrast and show estimated change over time (linear fixed-effects coefficients ± standard error) for the three conditions. Inset scatter plots show change over time for individual participants, estimated in single-participant models fitted post hoc; these have no relation to the statistical hypothesis test and are shown for illustrative purposes. a Proportion of time spent in the safe place (see Fig. 1b) linearly increases over time, and this increase is reduced in participants under valproate or pregabalin as compared to placebo (linear drug × time interaction, see Table 2). b Six secondary outcome measures. There is no significant difference between the two drugs in any measure, and Bayesian model comparison favours a model in which they have the same impact as compared to placebo. See Fig. S1 for a comparison with lorazepam. VPA valproate, PGB pregabalin, PLC placebo. *: significant linear drug × time interaction (for secondary outcomes after Bonferroni correction)

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