Cross-species anxiety tests in psychiatry: pitfalls and promises

Abstract

Behavioural anxiety tests in non-human animals are used for anxiolytic drug discovery, and to investigate the neurobiology of threat avoidance. Over the past decade, several of them were translated to humans with three clinically relevant goals: to assess potential efficacy of candidate treatments in healthy humans; to develop diagnostic tests or biomarkers; and to elucidate the pathophysiology of anxiety disorders. In this review, we scrutinise these promises and compare seven anxiety tests that are validated across species: five approach-avoidance conflict tests, unpredictable shock anticipation, and the social intrusion test in children. Regarding the first goal, three tests appear suitable for anxiolytic drug screening in humans. However, they have not become part of the drug development pipeline and achieving this may require independent confirmation of predictive validity and cost-effectiveness. Secondly, two tests have shown potential to measure clinically relevant individual differences, but their psychometric properties, predictive value, and clinical applicability need to be clarified. Finally, cross-species research has not yet revealed new evidence that the physiology of healthy human behaviour in anxiety tests relates to the physiology of anxiety symptoms in patients. To summarise, cross-species anxiety tests could be rendered useful for drug screening and for development of diagnostic instruments. Using these tests for aetiology research in healthy humans or animals needs to be queried and may turn out to be unrealistic.

Fig. 1. Human versions of the reviewed cross-species anxiety paradigms.

A Elevated plus maze: mixed-reality setup in which human participants explore a plank over a deep drop and another one that rests on a rocky ground. B Open field test. Participants explore, in reality or virtual reality, a large space up to the size of a soccer pitch. C Approach-avoidance conflict decision test. In a lottery, participants can decide on their desired probability of a neutral outcome (depicted by sun) and of a reward (red bar) coupled with an aversive sensory experience (depicted by rain). D Approach-avoidance conflict ‘scoop & run’ test. Participants move an avatar (green triangle) outside a safe place and back to collect a financial reward token (yellow rhombus), under threat of being caught by a virtual predator (grey circle) and losing tokens. E Approach-avoidance conflict ‘stay & play’ test. Participant move an avatar (green triangle) on a 24 × 16 grid to collect multiple to financial reward tokens (yellow rhombi), under threat of being caught by a virtual predator (grey circle) and losing all tokens. F NPU test. In a predictable condition, aversive outcomes are always cued, whereas they appear at random in an unpredictable condition. In a neutral condition, no aversive outcomes occur. The social intrusion test (no illustration) quantifies children’s behavioural inhibition in social contexts. A is reproduced from ref. [76]. B was created by Hazaña17 (https://commons.wikimedia.org/w/index.php?curid=16311903) under CC BY-SA 3.0. C is provided by courtesy of Dr Robin Aupperle. D–F are the author’s own work.