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Imaging studies have implicated altered functional connectivity in adults with major depressive disorder (MDD). Whether similar dysfunction is present in adolescent patients is unclear. The degree of resting-state functional connectivity (rsFC) may reflect abnormalities within emotional (‘hot’) and cognitive control (‘cold’) neural systems. Here, we investigate rsFC of these systems in adolescent patients and changes following cognitive behavioral therapy (CBT). Functional Magnetic Resonance Imaging (fMRI) was acquired from adolescent patients before CBT, and 24-weeks later following completed therapy. Similar data were obtained from control participants. Cross-sectional Cohort: From 82 patients and 34 controls at baseline, rsFC of the amygdala, anterior cingulate cortex (ACC), and pre-frontal cortex (PFC) was calculated for comparison. Longitudinal Cohort: From 17 patients and 30 controls with longitudinal data, treatment effects were tested on rsFC. Patients demonstrated significantly greater rsFC to left amygdala, bilateral supragenual ACC, but not with PFC. Treatment effects were observed in right insula connected to left supragenual ACC, with baseline case-control differences reduced. rsFC changes were significantly correlated with changes in depression severity. Depressed adolescents exhibited heightened connectivity in regions of ‘hot’ emotional processing, known to be associated with depression, where treatment exposure exerted positive effects, without concomitant differences in areas of ‘cold’ cognition.

Background: The POP Trial was a phase 1, open-label, rising-dose, randomised study that explored the safety and tolerability of calmangafodipir (superoxide dismutase mimetic) co-treatment with n-acetylcysteine (NAC) for paracetamol overdose. Methods: Patients were recruited at the Royal Infirmary of Edinburgh (8th June 2017-10th May 2018). Inclusion criterion: adults within 24 h of a paracetamol overdose that required NAC. Within each of 3 sequential cohorts, participants were randomly assigned, with concealed allocation, to NAC and a single intravenous calmangafodipir dose (n = 6) or NAC alone (n = 2). Calmangafodipir doses were 2, 5, or 10 μmol/kg. Participants, study and clinical teams were not blinded. The primary outcome was safety and tolerability. Secondary outcomes were alanine transaminase (ALT), international normalised ratio (INR), keratin-18, caspase-cleaved keratin-18 (ccK18), microRNA-122, and glutamate dehydrogenase (GLDH). (Clinicaltrials.gov:NCT03177395). Findings: All 24 participants received their allocated drug doses and were analysed. Primary endpoints: all participants experienced ≥1 adverse event (AE), most commonly gastrointestinal. Patients experiencing ≥1 serious adverse event (SAE): NAC alone, 2/6; NAC + calmangafodipir (2 μmol/kg), 4/6; NAC + calmangafodipir (5 μmol/kg), 2/6; NAC + calmangafodipir (10 μmol/kg), 3/6. No AEs or SAEs were probably or definitely calmangafodipir-related. Secondary safety outcomes demonstrated no differences between groups. With NAC alone, 2/6 had ALT > 100 U/L; with NAC + calmangafodipir, 0/18. No INR difference. Keratin-18 and ccK18 increased in the NAC alone group more than with calmangafodipir (baseline to 20 h fold change, NAC + calmangafodipir (5 μmol/kg) compared to NAC alone: 0.48 (95%CI 0.28–0.83)). microRNA-122 changes were similar to K18, GLDH was frequently undetected. Interpretation: Calmangafodipir was tolerated when combined with NAC and may reduce biomarkers of paracetamol toxicity.