Anxiety disorders are frequently diagnosed chronic, disabling conditions that impose enormous societal costs.
The main anxiety syndromes include panic disorder, agoraphobia, social anxiety disorder, generalized anxiety disorder, specific phobias, obsessive-compulsive disorder and post-traumatic stress disorder.
Treatment options, which include drugs acting on the GABA (γ-aminobutyric acid)–benzodiazepine and 5-hydroxytryptamine (5-HT; also known as serotonin) systems are available for most of these disorders. However, these compounds have limited efficacy and/or tolerability.
The urgent need for new, alternative treatments for anxiety has generated a vast amount of preclinical data and led to many drugs being taken though the laboratory to the clinic.
The clinical outcome of this huge effort has been disappointing, however, with laboratory rodent studies predicting very few promising new therapeutic leads.
This Review analyses the major trends from the preclinical data accrued over the past 50 years and highlights the most intensively investigated neurotransmitter systems: the GABA–benzodiazepine, serotonin, neuropeptide, glutamate and endocannabinoid systems.
We identify a number of key issues that may have hampered progress in the field.
Oft-cited explanations for the poor translational track record of preclinical anxiety studies include the lack of validity of the available rodent tests, the use of non-disease-susceptible animals, insufficient knowledge of the neurobiological anxiety systems and too much focus by pharmaceutical companies on single targets to find new anxiolytics.
Here, we offer recommendations for how anxiolytic drug discovery can be more effective going forward.
Anxiety disorders are the most prevalent group of psychiatric diseases, and have high personal and societal costs. The search for novel pharmacological treatments for these conditions is driven by the growing medical need to improve on the effectiveness and the side effect profile of existing drugs. A huge volume of data has been generated by anxiolytic drug discovery studies, which has led to the progression of numerous new molecules into clinical trials. However, the clinical outcome of these efforts has been disappointing, as promising results with novel agents in rodent studies have very rarely translated into effectiveness in humans. Here, we analyse the major trends from preclinical studies over the past 50 years conducted in the search for new drugs beyond those that target the prototypical anxiety-associated GABA (γ-aminobutyric acid)–benzodiazepine system, which have focused most intensively on the serotonin, neuropeptide, glutamate and endocannabinoid systems. We highlight various key issues that may have hampered progress in the field, and offer recommendations for how anxiolytic drug discovery can be more effective in the future.
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The authors thank S. Beeské for her editorial assistance.
The authors declare no competing financial interests.
A feature that is assessed (for a test or model of anxiety) by determining how closely the model or test resembles human anxiety symptoms (known as face validity); by determining whether the model or test reliably responds to clinically efficacious anxiety medications (known as predictive validity); and by determining the degree to which the model or test recruits the same underlying neurobiology as implicated in human anxiety (known as construct validity).
- Approach-avoidance conflict tests
Tests that generate anxiety-related behaviours in rodents by posing a conflict between a natural drive to explore a novel place and an inherent tendency to avoid new — particularly well-exposed — areas that may be dangerous.
- Pavlovian fear conditioning
A learning process by which neutral environmental stimuli, by virtue of association with a stressful event, evoke anxiety reactions. Fear extinction involves the learned inhibition of these reactions. Abnormalities in fear conditioning and extinction are thought to underlie anxiety disorders, notably specific phobias and post-traumatic stress disorder.
- Neural circuitry
A network of interconnected regions of the brain that mediate anxiety, including cortical structures (for example, the prefrontal cortex), limbic structures (for example, the amygdala, lateral septum and hippocampus) and the midbrain (for example, the dorsal raphe).
- Anxiety models
Models that generate lasting or permanently heightened anxiety; for example, by subjecting animals to chronic stress or by identifying or engineering 'high-anxiety' rodent strains. By contrast, simple tests or assays only transiently evoke an anxiety-like behaviour.
- Intermediate phenotype
A specific behavioural or neural feature of an anxiety disorder that might be more easily modelled in rodents than the whole constellation of symptoms found in an anxiety disorder.
- Anxiety traits
Persistent anxiety characteristics that manifest across a variety of situations and are considered to be an enduring feature of an individual.
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Griebel, G., Holmes, A. 50 years of hurdles and hope in anxiolytic drug discovery. Nat Rev Drug Discov 12, 667–687 (2013). https://doi.org/10.1038/nrd4075