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Treatment-resistant depression (TRD) is a serious problem in adolescents. Development and optimization of novel interventions for these youth will require a deeper knowledge of the neurobiology of depression. A well-established phenomenon of depression is an attention bias toward negativity and away from positivity that is evidenced behaviorally and neurally, but it is unclear how symptom reduction is related to changes to this bias. Neurobiological research using a treatment probe has promise to help discover the neural changes that accompany symptom improvement. Ketamine has utility for such research because of its known rapid and strong antidepressant effects in the context of TRD. Our previous study of six open-label ketamine infusions in 11 adolescents with TRD showed variable response, ranging from full remission, partial response, non-response, or clinical worsening. In this study, we examined the performance of these participants on Word Face Stroop (WFS) fMRI task where they indicated the valence of affective words superimposed onto either congruent or incongruent emotional faces before and after the ketamine infusions. Participants also completed a clinical assessment (including measurement of depression symptomology and anhedonia/pleasure) before and after the ketamine infusions. Following ketamine treatment, better WFS performance correlated with self-reported decreased depressive symptoms and increased pleasure. Analyses of corticolimbic, corticostriatal and default mode (DMN) networks showed that across networks, decreased activation during all conditions (congruent negative, congruent positive, incongruent negative, and incongruent positive) correlated with decreases in depressive symptoms and with increases in pleasure. These findings suggest that in adolescents with TRD, clinical improvement may require an attenuation of the negativity bias and re-tuning of these three critical neural networks to attenuate DMN and limbic regions activation and allow more efficient recruitment of the reward network. Lower activation across conditions may facilitate shifting across different salient emotional stimuli rather than getting trapped in downward negative spirals.

Neural and Behavioral Correlates of Clinical Improvement to Ketamine in Adolescents With Treatment Resistant Depression