| Objective:Generalized anxiety disorder(GAD)frequently emerges in childhood or adolescence and is among the most common mental disorders in adolescents.However,first-line pharmacological treatment for pediatric anxiety disorders—selective serotonin reuptake inhibitors(SSRIs)produces remission in only 50% of patients.In addition,it usually takes 6-8 weeks to evaluate whether patients respond or non-respond to SSRIs.Identifying the neurofunctional and neurostructural targets of SSRIs in adolescents with GAD might help us develop new drugs to improve the treatment response in this population;finding pretreatment or early-treatment neurofunctional or neurostructural markers that were associated with SSRI response could reduce the time to evaluate the treatment response and help patients switch to other pharmacotherapy or psychotherapy.Thus,we aimed to identify the neurofunctional and neurostructural targets of SSRIs,and examine whether pretreatment or early-treatment associated brain structural and functional measurements could predict treatment response in adolescents with GAD.Materials and Methods:Pretreatment and early-treatment(2 week into treatment)structural and functional MR images,during resting-state and while performing a continuous processing task with emotional and neutral distractors(CPT-END),were acquired from 51 adolescents(age: 12-17 years)with GAD who were randomized to 8-weeks double-blind escitalopram or placebo(1:1).The functional connectivity(FC)analyses were conducted to examine the neuroconnectivity between amygdala or its sub-regions and the rest voxels of wholebrain during resting-state and while viewing emotional pictures in each patient.In addition,longitudinal Free Surfer stream was performed to acquire the volume change of amygdala and its sub-regions,and cortical thickness change of whole-brain cerebral cortex.Full-factorial analysis was used to investigate the treatment effect of escitalopram on amygdala connectivity,two stage model was used to examine the escitalopram effect on cortical thickness and amygdala volume.Finally,correlation analysis was performed to explore whether pretreatment and early(week 2)treatmentrelated connectivity were associated with treatment response(improvement in anxiety severity)at week 8.Results:In adolescents with GAD,escitalopram changed the neuroconnectivity and neurostructural of amygdala and its subregions within the first two weeks of treatment.Specifically,(1)controlling for age and sex,escitalopram increased amygdalaventrolateral prefrontal cortex(vl PFC)connectivity compared to placebo.Exploratory analyses of amygdala subfields’ FC revealed connectivity of left basolateral amygdala(BLA)-vl PFC and superficial amygdala-posterior cingulate cortex(PCC)were also increased by escitalopram.This early FC change of amygdala-vl PFC and BLA-vl PFC predicted improvement in anxiety over 8 weeks of treatment in patients who received escitalopram;(2)compared to placebo,escitalopram enhanced FC of amygdalaventromedial prefrontal cortex(vm PFC)and amygdala-angular gyrus during emotion processing in adolescents with GAD.Importantly,baseline amygdala-vm PFC connectivity and escitalopram-induced increased amygdala-angular gyrus connectivity at week 2 both predicted the magnitude of subsequent clinical improvement in anxiety at the end of the trial;(3)escitalopram compared with placebo increased the rate of cortical thickness change in bilateral insula,and increased the rate of volume change in left basal nucleus,right cortical nucleus and corticoamygdaloid transition in adolescents with GAD.In detail,escitalopram increased cortical thickness of insula,increased volume of basal and cortical nuclei,and decreased volume of corticoamygdaloid transition.However,pretreatment and early-treatment of these structural alterations were not associated with improvement in anxiety.Conclusion:Our findings revealed that escitalopram,compared to placebo,changed brain structural morphometry and functional connectivity of amygdala and regions that subserved emotion processing including vl PFC,vm PFC,insula,PCC and angular gyrus within the first 2 weeks of treatment in adolescents with GAD.In addition,pretreatment or early-treatment changes of amygdala-vl PFC,BLA-vl PFC,amygdalavm PFC and amygdala-angular gyrus connectivity predicted subsequent clinical improvement.These findings suggest amygdala connectivity with hubs of emotion processing and regulation might be the targets of acute SSRI treatment.Moreover,pretreatment and early-treatment connectivity of amygdala could be leveraged as biomarkers of SSRI response in adolescents with GAD. |
PDF Full Text Request