Biopsychosocial correlates of resting and stress-reactive salivary GDF15: preliminary findings.

In recent years, the rate of anxiety disorder diagnoses has rapidly increased both nationally and worldwide (; ). Between 1990 and 2019 there was a 55% increase in anxiety disorders globally (), with an additional 25% increase observed in the prevalence of anxiety and related disorders as a direct result of the COVID-19 pandemic (). Increases in diagnoses are comparable among all age groups and across biological sex, with anxiety being the second-most common psychiatric disease following depression (for a review, see ). These statistics do not account for those living undiagnosed or misdiagnosed, capturing only a fraction of these disorders’ impact. Due to the significant disruption in daily functioning caused by anxiety-based disorders, developing effective treatments is paramount. Like many other psychiatric conditions, pharmacotherapy is a common route of treatment with antidepressant selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) being widely prescribed to treat anxiety (). However, these medications often have a delayed latency accompanied by adverse side-effects at the time of introduction, leading to difficulties sustaining treatment compliance. Psychotherapies or combination therapies are therefore found to be more effective in mitigating symptoms, with cognitive behavioral therapy (CBT) being the most well-studied and widely-implemented (; ). Exposure therapy is a well-known form of CBT used to reduce fear- and anxiety-related symptoms in anxiety disorders. In a typical version of this procedure, an individual is increasingly exposed to their specific anxiety-inducing stimulus in a controlled, safe setting to aid in the reduction of fear to that stimulus (). Preclinical rodent studies use a similar procedure called extinction to reduce fear behaviors observed following fear conditioning. In extinction, repeated, unreinforced exposure to a conditional stimulus (CS; e.g., a tone) that was previously paired with an unconditional stimulus (US; e.g., a footshock) results in the formation of a new CS-No US association (Bouton, 2022). Not presenting a US following a CS when one is expected introduces a high amount of prediction error and creates a new, inhibitory memory (). Successful retrieval of the extinction memory is crucial for successfully mitigating fear symptoms (; ). The presence of competing excitatory (learned in acquisition) and inhibitory (learned in extinction) memories could provide a possible explanation for the failure of extinction retrieval in vulnerable populations, including adolescent () and aged individuals (), as well as the high incidence of fear relapse of a previously extinguished behavior (). Relapse can be described as a reemergence of symptoms following extinction, and can occur due to removal from the extinction context (i.e., renewal) or re-exposure to the original stimulus (i.e., reinstatement) ().