Neural Correlates of Antidepressant Treatment Response in Adolescents with Major Depressive Disorder

Abstract

Objective: The neural changes underlying response to antidepressant treatment in adolescents are unknown. Identification of neural change correlates of treatment response could (1) aid in understanding mechanisms of depression and its treatment and (2) serve as target biomarkers for future research.

Method: Using functional magnetic resonance imaging, we examined changes in brain activation and functional connectivity in 13 unmedicated adolescents with major depressive disorder (MDD) before and after receiving treatment with a selective serotonin reuptake inhibitor medication for 8 weeks. Specifically, we examined brain activation during a negative emotion task and resting-state functional connectivity (RSFC), focusing on the amygdala to capture networks relevant to negative emotion. We conducted whole-brain analyses to identify how symptom improvement was related to change in brain activation during a negative emotion task or amygdala RSFC.

Results: After treatment, clinical improvement was associated with decreased task activation in rostral and subgenual anterior cingulate cortex and increased activation in bilateral insula, bilateral middle frontal cortices, right parahippocampus, and left cerebellum. Analysis of change in amygdala RSFC showed that treatment response was associated with increased amygdala RSFC with right frontal cortex, but decreased amygdala RSFC with right precuneus and right posterior cingulate cortex.

Conclusion: The findings represent a foothold for advancing understanding of pathophysiology of MDD in adolescents by revealing the critical neural circuitry changes that underlie a positive response to a standard treatment. Although preliminary, the present study provides a research platform for future work needed to confirm these biomarkers at a larger scale before using them in future target engagement studies of novel treatments.

Keywords: adolescent; antidepressants; depression; fMRI; treatment response.

FIG. 1.

Relationship between change in brain activation to negative emotion after SSRI treatment and improvement in depression symptoms. Clusters with warm colors indicate brain regions where greater improvement in depression symptoms was associated with greater decreases in task activation. These regions include bilateral rostral and subgenual ACC (BA 32 and 25) and inferior frontal cortex (BA 11). Clusters with cool colors indicate brain regions where improvement in depression symptoms was associated with an increase in brain activation (right parahippocampus, bilateral insula (BA 13), bilateral middle frontal cortices (BA 8), and left cerebellum. (a–e) Correspond to descriptions in Table 2. ACC, anterior cingulate cortex; BA, Brodmann area; SSRI, selective serotonin reuptake inhibitor.

FIG. 2.

Relationship between change in amygdala RSFC after SSRI treatment and improvement in depression symptoms. Clusters with warm colors indicate brain regions where greater improvement in depression symptoms was associated with greater decreases in amygdala RSFC. One warm cluster was observed in the right posterior cingulate/precuneus (BA 31). Clusters with cool colors indicate brain regions where improvement in depression symptoms was associated with an increase in amygdala RSFC. These regions include right medial and middle frontal gyri (BA 8). (a–c) Correspond to descriptions in Table 2. BA, Brodmann area; RSFC, resting-state functional connectivity SSRI, selective serotonin reuptake inhibitor.