Towards new approaches to disorders of fear and anxiety

Abstract

Fear and anxiety are debilitating conditions that affect a significant number of individuals in their lifetimes. Understanding underlying mechanisms of these disorders affords us the possibility of therapeutic intervention. Such clarity in terms of mechanism and intervention can only come from an amalgamation of research from human to animal studies that attempt to mimic the human condition, both of which are discussed in this review. We begin by presenting an outline of our current understanding of the neurobiological basis of fear and anxiety. This outline spans various levels of organization that include the circuitry, molecular pathways, genetic and epigenetic components of fear and anxiety. Using these organizational levels as a scaffold, we then discuss strategies that are currently used to ameliorate these disorders, and forecast future interventions that hold therapeutic promise. Among these newer promising treatments, we include, optogenetic, pharmacological, and extinction-based approaches, as well as lifestyle modifications, with combinatorial treatment regimens of these holding the most promise.

Figure 1. Structural and Molecular Pathways Involved in Fear and Anxiety

A schematic mammalian brain is shown in which prefrontal cortex (PFC) and sensory cortex interact with hippocampal (HP), bed nucleus of the stria terminalis (BNST), amygdala (AM) and hypothalamic (HYP) circuits to mediate stress, anxiety, and fear responses.

Figure 2. The Hard-wired ‘Fear Reflex’ Underlies the Symptoms of Fear and Panic Responses

Neural connectivity between the Central Amygdala outputs (CeA) to brainstem and other subcortical areas activates a known and increasingly well-understood series of pathways which mediate the differential fear reflex patterns that are experienced as a fear or panic-attack in humans with anxiety and fear-related disorders. (modified from [80])

Figure 3. Current and Promising New Approaches to Treatments for Anxiety and Fear-Related Disorders

Currently utilized treatments include antidepressants (targeting serotonin, norepinephrine, and dopamine monoaminergic pathways), GABA-acting benzodiazepines, and beta-adrenergic receptor blockers, as well as cognitive-behavioral therapies. However, all of these treatments have limited efficacy, and new direct and combined treatments specifically targeting known neural pathways underlying fear and anxiety are on the horizon.