Abstract
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.
Highlights
Depression, the second leading cause of disability globally, commonly arises during the adolescent period [1]
Inclusion criteria included a current diagnosis of Major Depressive Disorder (MDD), a Children’s Depression Rating Scale-Revised [CDRS-R [31]] raw score >40, stable psychotherapy for 2 months (Years in therapy: M = 3.26; SD = 2.66), stable psychotropic medication dose for 2 months, and evidence of treatment resistance
Change in TEPS anticipatory (TEPS-A) and TEPS-C were strongly positively correlated (r = .85, p = .001), so we focused on TEPS total score in the following analyses
Summary
Depression, the second leading cause of disability globally, commonly arises during the adolescent period [1]. While evidence-based treatments are available, such as cognitive behavioral therapy and selective serotonin inhibitor antidepressants, up to 40% of adolescents with depression fail to respond to these interventions [2], emphasizing the need to discover new efficacious treatments. Development and optimization of novel interventions will require a deeper knowledge of the neurobiology of depression and the key neural changes that accompany treatment response. Examination of neural and behavioral indices in the context of a clinical trial provides the opportunity to identify the key brain changes that accompany clinical improvement. In our recent pilot study testing open-label ketamine in adolescents with depression, there was significant variability in response at 2 weeks, ranging from full remission, partial response, non-response, or clinical worsening [7]. We had expected more consistently positive outcomes, this variability provides an advantage for identifying neurobehavioral correlates of symptom improvement
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