Seewoo, Bhedita J.

Abstract Background Despite its morbidity and mortality, the neurobiology of treatment-resistant depression (TRD) in adolescents and the impact of treatment on this neurobiology is poorly understood. Methods Using automatic segmentation in FreeSurfer, we examined brain magnetic resonance imaging baseline volumetric differences among healthy adolescents (n = 30), adolescents with major depressive disorder (MDD) (n = 19), and adolescents with TRD (n = 34) based on objective antidepressant treatment rating criteria. A pooled subsample of adolescents with TRD were treated with 6 weeks of active (n = 18) or sham (n = 7) 10-Hz transcranial magnetic stimulation (TMS) applied to the left dorsolateral prefrontal cortex. Ten of the adolescents treated with active TMS were part of an open-label trial. The other adolescents treated with active (n = 8) or sham (n = 7) were participants from a randomized controlled trial. Results Adolescents with TRD and adolescents with MDD had decreased total amygdala (TRD and MDD: −5%, P = .032) and caudal anterior cingulate cortex volumes (TRD: −3%, P = .030; MDD: −.03%, P = .041) compared with healthy adolescents. Six weeks of active TMS increased total amygdala volumes (+4%, P < .001) and the volume of the stimulated left dorsolateral prefrontal cortex (+.4%, P = .026) in adolescents with TRD. Conclusions Amygdala volumes were reduced in this sample of adolescents with MDD and TRD. TMS may normalize this volumetric finding, raising the possibility that TMS has neurostructural frontolimbic effects in adolescents with TRD. TMS also appears to have positive effects proximal to the site of stimulation.

Objectives: Prior studies demonstrate elevated cortical glutamate (Glu) in patients with bipolar disorder (BD). Studies assessing neurochemistry in early stages of bipolar illness before the emergence of manic symptoms are lacking. This study aimed to examine neurochemical correlates measured by proton magnetic resonance spectroscopy ( 1 H-MRS) and a dimensional measure of bipolarity in a sample of depressed adolescents. Methods: Adolescent participants (aged 13–21 years) underwent a semistructured diagnostic interview and clinical assessment, which included the General Behavior Inventory Parent Version (P-GBI), a 73-item, parent-rated assessment of symptoms and behaviors. 1 H-MRS scans of a left dorsolateral prefrontal cortex (L-DLPFC) voxel (8 cm 3 ) were collected using a two-dimensional J -averaged sequence to assess N -acetylaspartate (NAA), Glu, Glx (glutamate + glutamine), and NAA/Glx concentrations. We used generalized linear models to assess the relationships between P-GBI scores and metabolite levels in L-DLPFC. Results: Thirty-six participants (17 healthy controls, 19 depressed) underwent 1 H-MRS scans and clinical evaluation with the P-GBI. There was a significant negative relationship between P-GBI score and L-DLPFC NAA/Glx in the whole sample. However, the magnitude of the effect was small and statistical significance was lost after correcting for multiple comparisons. Conclusions: These preliminary results suggest that NAA/Glx may have utility as a marker of bipolar traits in healthy and depressed adolescents. If replicated, 1 H-MRS measures of glutamatergic metabolism anomalies might have a role in identifying depressed adolescents at risk for mixed symptom presentations or BD. Identifying bipolarity in the early stages of the disease would have a significant impact on treatment planning and prognosis. Further longitudinal studies should examine neurochemical correlates of mood state during the developmental emergence of BD.