A single dose of fluoxetine reduces neural limbic responses to anger in depressed adolescents

Abstract

Depression in adolescence is frequently characterised by symptoms of irritability. Fluoxetine is the antidepressant with the most favourable benefit:risk ratio profile to treat adolescent depression, but the neural mechanisms underlying antidepressant drugs in the young brain are still poorly understood. Previous studies have characterised the neural effects of long-term fluoxetine treatment in depressed adolescents, but these are limited by concurrent mood changes and a lack of placebo control. There is also recent evidence suggesting that fluoxetine reduces the processing of anger in young healthy volunteers, which is consistent with its effect for the treatment of irritability in this age group, but this remains to be investigated in depressed adolescents. Here we assessed the effects of a single, first dose of 10 mg fluoxetine vs. placebo on neural response to anger cues using fMRI in a sample of adolescents with Major Depressive Disorder (MDD) who had been recently prescribed fluoxetine. As predicted, adolescents receiving fluoxetine showed reduced activity in response to angry facial expressions in the amygdala-hippocampal region relative to placebo. Activity in the dorsal anterior cingulate cortex (dACC) was also increased. No changes in symptoms were observed. These results demonstrate, for the first time in depressed adolescents, that fluoxetine has immediate neural effects on core components of the cortico-limbic circuitry prior to clinical changes in mood. The effect on anger is consistent with our previous work and could represent a key mechanism through which fluoxetine may act to alleviate irritability symptoms in adolescent depression.

Fig. 1. Whole-brain activation in response to anger vs. baseline (fixation) across groups.

Sagittal, coronal and axial images depicting neural activation in response to anger vs. baseline (fixation) across groups. Images thresholded at Z > 2.3, p < 0.05, corrected

Fig. 2. Whole-brain activation in response to angry vs. happy faces.

a Sagittal, coronal and axial images depicting significantly reduced activation in the fluoxetine group for the anger vs. happiness contrast in a left temporolimbic cluster extending into the amygdala and hippocampus (peak voxels: x = −30, y = −24, z = −14; Z = 3.58; voxel size: 315). Images thresholded at Z > 2.3, p < 0.05, corrected. b BOLD percent signal change extracted from the significant left temporolimbic cluster in response to angry vs. happy faces. Error bars show standard error of the mean

Fig. 3. Mean percentage signal change from the anatomical mask in the amygdala.

Mask from right hemisphere, created using Harvard-Oxford Atlas. Bars represent the mean percentage of signal change (%). Error bars show the standard error of the mean

Fig. 4. Mean percentage signal change from the anterior cingulate cortex (ACC).

Top refers to dorsal ACC (dACC) and bottom to ventral ACC (vACC). Masks (8 mm spheres) were created based on the local maxima from Kujawa and colleagues and Beaver and colleagues: x = −4, y = 30, z = 16 (dACC), x = −18, y = 39, z = −12 (vACC). Sagittal view. Bars represent the mean percentage of signal change (%). Error bars show the standard error of the mean