From recent advances in underlying neurocircuitry of fear and anxiety to promising pharmacotherapies for PTSD: The saga of heart, sex and the developing brain

Available pharmacotherapies for anxiety disorders and post-traumatic stress-disorder (PTSD) have limited efficacy, but no new anxiolytic drug has been approved for treatment since the 1980s. In this issue of Neuropharmacology on "Fear, anxiety and PTSD: from cellular mechanisms to translational approaches", we review the currently recommended pharmacotherapy for PTSD and discuss promising pharmacotherapies being revisited or newly developed. Novel strategies for pharmaceuticals in PTSD treatment include the use of serotonergic psychedelics as low-dose adjunct therapies combined with psychotherapy. We also discuss the use of glucocorticoids targeting the temporal window shortly following trauma exposure to interfere with fear memory consolidation. Although many factors have impeded progress in pharmacotherapy development for anxiety disorders and PTSD, we highlight three: (1) the sparsity of preclinical studies investigating the neurobiology of fear processing in female animal models despite the higher prevalence of anxiety disorders in women, (2) the poor implementation of the knowledge of how stress affects fear circuitry development across the lifetime into clinical practice, and (3) our paucity of knowledge of canonical fear circuitry in adaptive vs. maladaptive fear processing. Finally, we emphasize the functional link between interoceptive signals and emotion regulation and discuss how these interoceptive signals may be an inroad into PTSD treatment, which is often accompanied by cardiovascular dysregulation. A better understanding of the neurobiological underpinnings of adaptive and maladaptive fear processing is critical for identifying risk factors that will spur the development of sex-and developmental trauma-specific interventions, ushering in a new era of precision medicine for anxiety disorders and PTSD.