Brain entropy and neurotrophic molecular markers accompanying clinical improvement after ketamine: Preliminary evidence in adolescents with treatment-resistant depression

Brain entropy and neurotrophic molecular markers accompanying clinical improvement after ketamine: Preliminary evidence in adolescents with treatment-resistant depression

Background: Current theory suggests that treatment-resistant depression (TRD) involves impaired neuroplasticity resulting in cognitive and neural rigidity, and that clinical improvement may require increasing brain flexibility and adaptability. Aims: In this hypothesis-generating study, we sought to...

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Published in:Journal of psychopharmacology (Oxford) Vol. 35; no. 2; pp. 168 - 177
Main Authors: Roy, Abhrajeet V, Thai, Michelle, Klimes-Dougan, Bonnie, Westlund Schreiner, Mindy, Mueller, Bryon A, Albott, Christina Sophia, Lim, Kelvin O, Fiecas, Mark, Tye, Susannah J, Cullen, Kathryn R
Format: Journal Article
Language:English
Published: London, England SAGE Publications 01-02-2021
Sage Publications Ltd
Subjects:
Adaptability
Adolescents
Brain mapping
Clinical trials
Cognitive ability
Entropy
Flexibility
Functional magnetic resonance imaging
Glycogen
Glycogen synthase
Insulin
Ketamine
Leukocytes (mononuclear)
Magnetic resonance imaging
Mental depression
Neural plasticity
Neuroimaging
Nucleus accumbens
Peripheral blood mononuclear cells
Phosphorylation
Rapamycin
Teenagers
TOR protein
mTOR/GSK3β
Ketamine
entropy
depression
adolescents
neuroplasticity
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Summary:Background: Current theory suggests that treatment-resistant depression (TRD) involves impaired neuroplasticity resulting in cognitive and neural rigidity, and that clinical improvement may require increasing brain flexibility and adaptability. Aims: In this hypothesis-generating study, we sought to identify preliminary evidence of brain flexibility correlates of clinical change within the context of an open-label ketamine trial in adolescents with TRD, focusing on two promising candidate markers of neural flexibility: (a) entropy of resting-state functional magnetic resonance imaging (fMRI) signals; and (b) insulin-stimulated phosphorylation of mammalian target of rapamycin (mTOR) and glycogen synthase-3-beta (GSK3β) in peripheral blood mononuclear cells. Methods: We collected resting-state functional magnetic resonance imaging data and blood samples from 13 adolescents with TRD before and after a series of six ketamine infusions over 2 weeks. Usable pre/post ketamine data were available from 11 adolescents for imaging and from 10 adolescents for molecular signaling. We examined correlations between treatment response and changes in the central and peripheral flexibility markers. Results: Depression reduction correlated with increased nucleus accumbens entropy. Follow-up analyses suggested that physiological changes were associated with treatment response. In contrast to treatment non-responders (n=6), responders (n=5) showed greater increase in nucleus accumbens entropy after ketamine, together with greater post-treatment insulin/mTOR/GSK3β signaling. Conclusions: These data provide preliminary evidence that changes in neural flexibility may underlie symptom relief in adolescents with TRD following ketamine. Future research with adequately powered samples is needed to confirm resting-state entropy and insulin-stimulated mTOR and GSK3β as brain flexibility markers and candidate targets for future clinical trials. Clinical trial name: Ketamine in adolescents with treatment-resistant depression URL: https://clinicaltrials.gov/ct2/show/NCT02078817 Registration number: NCT02078817
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SJ Tye and KR Cullen contributed equally as senior authors on this manuscript
ISSN:0269-8811
1461-7285
DOI:10.1177/0269881120928203