A Double-Blind Randomized Trial to Investigate Mechanisms of Antidepressant-Related Dysfunctional Arousal in Depressed or Anxious Youth at Familial Risk for Bipolar Disorder

Abstract

Antidepressants are standardly used to treat moderate to severe symptoms of depression and/or anxiety in youth but may also be associated with rare but serious psychiatric adverse events such as irritability, agitation, aggression, or suicidal ideation. Adverse events are especially common in youth with a family history of bipolar disorder (BD) who are at heightened risk for dysfunction in neurobiological systems that regulate emotion and arousal. To further understand this phenomenon, this study will examine (a) baseline risk factors associated with dysfunctional arousal in a sample of youth at high-risk for BD treated with or without an antidepressant, (b) whether antidepressant-related changes in arousal are mediated by changes in prefrontal-limbic circuitry, and (c) whether pharmacogenetic factors influence antidepressant-related changes in arousal. High-risk youth (aged 12–17 years with moderate to severe depressive and/or anxiety symptoms and at least one first-degree relative with bipolar I disorder) will be randomized to receive psychotherapy plus escitalopram or psychotherapy plus placebo. Neuroimaging and behavioral measures of arousal will be collected prior to randomization and at 4 weeks. Samples for pharmacogenetic analysis (serum escitalopram concentration, CYP2C19 metabolizer phenotype, and HTR2A and SLC6A4 genotypes) will be collected at 8 weeks. Youth will be followed for up to 16 weeks to assess change in arousal measures.

Aberrant brain network topology in youth with a familial risk for bipolar disorder: a task‐based fMRI connectome study

“…Fifty‐seven socio‐demographically matched typically developing healthy controls without any known personal or family history of a psychiatric disorder were also recruited. The exclusion criteria for high‐risk youth included those having a history of bipolar I or II disorder; having previous exposure to antidepressants; having a diagnosis of autism spectrum disorder, obsessive‐compulsive disorder, post‐traumatic stress disorder, Tourette's disorder, or any psychotic disorder; having intellectual disability (full scale IQ < 70); having neurological illness (e.g., epilepsy); having substance or alcohol abuse or dependence disorders in the past 4 months; having an unstable medical or psychiatric disorder that required emergency treatment; being pregnant; or having MRI contraindications (detailed inclusion and exclusion criteria are provided in Appendix S1) (Honeycutt et al., 2022). After informed assent and consent were obtained from participants and their legal guardians, respectively, participants underwent high‐resolution 3D T1‐weighted image scanning for anatomical localization and fMRI scanning during performance of the CPT‐END task after thorough clinical evaluations and informed assent.…”

“…Fifty-seven socio-demographically matched typically developing healthy controls without any known personal or family history of a psychiatric disorder were also recruited. (Honeycutt et al, 2022). After informed assent and consent were obtained from participants and their legal guardians, respectively, participants underwent high-resolution 3D T1-weighted image scanning for anatomical localization and fMRI scanning during performance of the CPT-END task after thorough clinical evaluations and informed assent.…”

“…Herein, we recruited and characterized a large cohort of depressed and/or anxious youth with a familial risk for developing BD who are na€ ıve to antidepressant exposure (Honeycutt et al, 2022), with the ultimate objective to investigate the underlying brain mechanisms associated with antidepressant-related dysfunctional arousal. A study of symptomatic individuals with a familial risk for BD enables investigating the neural substrates' underlying risk for BD and other mood disorder and related outcomes.…”