Association between poor tolerability of antidepressant treatment and brain functional activation in youth at risk for bipolar disorder

Abstract

Objective: To investigate whether poor antidepressant tolerability is associated with functional brain changes in children and adolescents of parents with bipolar I disorder (at-risk youth). Methods: Seventy-three at-risk youth (ages 9-20 years old) who participated in a prospective study and had an available baseline functional magnetic resonance imaging (fMRI) scan were included. Research records were reviewed for the incidence of adverse reactions related to antidepressant exposure during follow-up. The sample was divided among at-risk youth without antidepressant exposure (n=21), at-risk youth with antidepressant exposure and no adverse reaction (n=12), at-risk youth with antidepressant-related adverse reaction (n=21), and healthy controls (n=20). The fMRI task was a continuous performance test with emotional distracters. Region-of-interest mean activation in brain areas of the fronto-limbic emotional circuit was compared among groups. Results: Right amygdala activation in response to emotional distracters significantly differed among groups (F 3,66 = 3.1, p = 0.03). At-risk youth with an antidepressant-related adverse reaction had the lowest amygdala activation, while at-risk youth without antidepressant exposure had the highest activation (p = 0.004). Conclusions: Decreased right amygdala activation in response to emotional distracters is associated with experiencing an antidepressant-related adverse reaction in at-risk youth. Further studies to determine whether amygdala activation is a useful biomarker for antidepressant-related adverse events are needed.

Pharmacogenomics as a Tool in Addressing Genetic VariationDependent Adverse Drug Reactions

“…These adverse effects can also manifest as poor tolerability in youth at risk for bipolar disorder, as evidenced by decreased right amygdala activation in response to emotional distracters. In addition to the physical manifestations of ADRs, the impact of antidepressants on mental health and behavior is also a significant concern (Nery et al, 2021). For instance, decreased right amygdala activation in response to emotional distracters has been associated with experiencing antidepressant-related adverse reactions in at-risk youth, highlighting the potential impact on brain functional activation (Nery et al, 2021).…”

“…In addition to the physical manifestations of ADRs, the impact of antidepressants on mental health and behavior is also a significant concern (Nery et al, 2021). For instance, decreased right amygdala activation in response to emotional distracters has been associated with experiencing antidepressant-related adverse reactions in at-risk youth, highlighting the potential impact on brain functional activation (Nery et al, 2021). Additionally, Williams et al (2015) suggested that amygdala reactivity to emotional faces may help predict general and medication-specific responses to antidepressant treatment, indicating the potential of amygdala probes in informing the personal selection of antidepressant treatments.…”

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

“…In contrast, one study identified a significant difference in mean activation in the right amygdala among youth with a familial risk for bipolar disorder treated with antidepressants, at-risk youth without antidepressant use, and healthy controls. Specifically, youth at risk for bipolar disorder who were treated with antidepressants and experienced an antidepressant-related adverse reaction had the lowest amygdala activation at baseline [ 50 ]. These findings suggest that in youth at risk for bipolar disorder, baseline dysregulation of amygdala activity may be exacerbated by antidepressants and inadequately moderated by prefrontal regulation of amygdala activity, leading to adverse behavioral reactions such as aggression, impulsivity, and irritability [ 50 ].…”

“…Specifically, youth at risk for bipolar disorder who were treated with antidepressants and experienced an antidepressant-related adverse reaction had the lowest amygdala activation at baseline [ 50 ]. These findings suggest that in youth at risk for bipolar disorder, baseline dysregulation of amygdala activity may be exacerbated by antidepressants and inadequately moderated by prefrontal regulation of amygdala activity, leading to adverse behavioral reactions such as aggression, impulsivity, and irritability [ 50 ]. Though replicable findings describe consistent patterns of neural activity and modulation, antidepressants may exert dynamic effects on the brain which require repeated assessment over time.…”